\r\n\t \r\n\tComputer graphics are not entirely an original topic, because it defines and solves problems using some already established techniques such as geometry, algebra, optics, and psychology. The geometry provides a framework for describing 2D and 3D space, while the algebraic methods are used for defining and evaluating equality related to the specific space. The science of optics enables the application of the model for the description of the behavior of light, while psychology provides models for visualization and color perception. \r\n\t \r\n\t3D computer graphics (or 3D graphics, three-dimensional computer graphics, three-dimensional graphics) is a term describing the different methods of creating and displaying three-dimensional objects by using computer graphics. \r\n\tThe first types of graphic interpretations were put in the plane (two-dimensional 2D). Requirements for a universal interpretation led to a three-dimensional (3D) interpretation content. From these creations have arisen applied mathematics and information disciplines of graphic interpretation of content - computer graphics. It relies on the principles of Mathematics, Descriptive Geometry, Computer Science and Applied Electronics. \r\n\t \r\n\t3D computer graphics or three-dimensional computer graphics use a three-dimensional representation of geometric data (often in terms of the Cartesian coordinate system) that is stored on a computer for the purpose of doing the calculation and creating 2D images. The images that are made can be stored for later use (probably as animation) or can be displayed in real-time. \r\n\t \r\n\tObjects within the 3D computer graphics are often called 3D models. Unlike rendered (generated) images, data that are ""tied"" to the model are inside graphic files. The 3D model is a mathematical representation of a random three-dimensional object. The model can be displayed visually as a two-dimensional image through a process called 3D rendering or can be used in non-graphical computer simulations and calculations. With 3D printing, models can be presented in real physical form. \r\n\t \r\n\tComputer graphics have remained one of the most interesting areas of modern technology, and it is the area that progresses the fastest. It has become an integral part of both application software, and computer systems in general. Computer graphics is routinely applied in the design of many products, simulators for training, production of music videos and television commercials, in movies, in data analysis, in scientific studies, in medical procedures, and in many other fields.
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1. Introduction
Sarcopenia and frailty are two common geriatric conditions that may co-occur within a single individual with aging. Frailty is a heterogeneous clinical condition depended on different domains. Definitions of frailty includes fried physical frailty phenotype (weight loss, exhaustion, physical inactivity, handgrip strength, and walk time) [1] and frailty index (use of walking aid, activities of daily living, incontinence, cognitive impairment, and multiple other components) [2]. Cognition performance decline is considered as a domain in Frailty index, but as “cognitive frailty” phenotype when physical frailty and potentially reversible cognitive impairment simultaneously occur [3]. Sarcopenia refers to decline in skeletal muscle mass and function, which includes primary sarcopenia, or age-related loss of muscle mass and function decline, and secondary sarcopenia resulting from nutrition, activity, and disease-related loss of muscle mass [4]. Sarcopenia is different from cachexia, which combines the loss of both muscle and fat. Obviously, physical frailty and sarcopenia share the core components, physical function impairment (weakness, slow walking speed, and balance problems), and sarcopenia is considered as the biological substrate and the pathway of physical frailty development [5, 6].
Although it is a controversy, sarcopenia and frailty are two separate conditions based on their definitions, and outpatients with sarcopenia were more likely to be more frail than frail outpatients to be sarcopenic [7]. Skeletal muscle is not only a component of muscloskeletal system but also an endocrine organ. Two components of sarcopenia also obviously contribute to frailty, a geriatric syndrome that has been defined as a multisystem impairment characterized by decreased reserve associated with increased vulnerability to stressors. First, the loss of muscle mass plays a critical role in unintentional weight loss of frailty in the elderly. Second, age-related loss of muscle strength, commonly referred as dynapenia, was associated with both sarcopenia and frailty [8]. Sarcopenia and frailty had the sensitivity and specificity for dynapenia of 33 and 89%, 17 and 98%, respectively. A longitudinal aging study with 731 community-dwelling older people demonstrated that dynapenia was related to the cognitive impairment [9]. Thus, dynapenia is also the important factor responsible for frailty. Moreover, muscle cross-talks with other tissues and organs by myokines in an endocrine manner to mediate metabolism and promote aging, diseases, and frailty. Here, we review the epidemiological evidence and pathophysiological basis of skeletal muscle aging, or primary sarcopenia, that result in frailty and potential target molecules of intervention. Particularly, we focus on the pathophysiological basis of sarcopenia, including age-related changes of nutrient and stress sensors, positive and negative regulators of muscle growth, and the maintenance of muscle mass and function. Moreover, we also summarize the underlying mechanisms of sarcopenia accelerating systemic aging, frailty, and age-related diseases. Finally, we looked for the potential target molecules of intervention of sarcopenia according to the pathophysiological basis and relevant signal pathways.
2. From Sarcopenia to frailty: the pathophysiological basis
2.1. From sarcopenia to physical and cognitive frailty: the epidemiological evidence
Frailty is heterogeneous and contains physical and cognitive multiple domains. In this context, the concept of “Cognitive frailty” becomes essential. It refers to simultaneous presence of physical frailty and potentially reversible cognitive impairment but without dementia [3]. Cognitive frailty includes reversible and potentially reversible subtypes [10] and may represent a precursor of neurodegenerative processes [10]. The link between physical function and cognitive decline provides important targets to develop effective preventive strategies in earlier cognitive impairment stages [3, 11, 12].
Epidemiological studies suggested that sarcopenia increases the risks of both physical frailty and cognitive impairment. Loss of muscle mass and strength is associated with increased dependence, frailty, and mortality. Low appendicular lean mass related to body mass index could detect patients at risk for frailty [13]. A cross-sectional study with small subjects, 273 Japanese community-dwelling older women aged >65 years showed that sarcopenia was related only with prefrailty and frailty, and cognitive decline was related to frailty [14]. However, several studies showed an association between sarcopenia parameters and cognitive impairment. Low handgrip strength was shown to correlate with a decrease in Mini Mental State Examination (MMSE) score [15]. Other studies also reported an association between handgrip strength and the risk of Alzheimer disease and the rate of cognitive decline [16–18]. In prospective studies, a decrease in physical performance in relation to future dementia was demonstrated [19, 20]. Subjects aged >65 years who scored low in a physical performance test had a three-times higher risk of developing dementia at a 6-year follow-up [21]. Recently, the new concept of “Motoric Cognitive Risk (MCR) syndrome” was defined as having mild cognitive impairment (MCI) and slow gait, supporting the common underlying mechanism in physical and cognitive impairment [22]. MCR offered further benefit on predicting dementia than MCI or slow gait alone. A recent study demonstrated an association between increased risk of cognitive impairment, mainly MCI, and poor lower extremity function [21].
2.2. Aging promotes sarcopenia and frailty
Factors relating to skeletal muscle mass and strength changes include the loss of motor units innervating muscle, age-related hormone changes, muscle hypoxia resulting from atherosclerosis and chronic proinflammatory status, decreased physical activity and protein intake, age-related insulin resistance, and mitochondrial dysfunction [23]. Aging leads to a preferential reduction of type II myofiber size. There is a significant loss of type II muscle fibers, lower satellite cell density, and lower satellite cell/fiber ratio in older individuals with sarcopenia [24]. The loss of motor units innervating muscle, especially type II myofibers [25], and the decreased blood flow to muscle [26] results in the loss of muscle mass. Meanwhile, many elderly population with insulin resistance who maintains the sensitivity of glucose metabolism, but not protein synthesis, show age-related anabolic resistance, meaning the reduced muscle protein synthesis [27, 28]. However, muscle of older individuals with type 2 diabetes [29] metabolic syndrome [30] demonstrated a significant low proportion of type I fibers that is positively associated with the severity of insulin resistance. Thus, the loss of muscle mass and the alterations of myofiber type proportion due to insulin resistance could potentially affect whole body glucose homeostasis [31]. Age-related hormone changes, for example, the decline of anabolic hormone testosterone leads to the loss of both muscle mass and strength [32]. The decline in both growth hormone and insulin-like growth factor 1 are related to the loss of muscle mass but not muscle strength [33]. Muscle hypoxia results from atherosclerosis and chronic proinflammatory status leads to the loss of both muscle mass and strength [25]. Other factors, decreased physical activity and protein intake, also involve in the loss of muscle mass.
Age-related decline of the levels of 25(OH) vitamin D due to a decreased production of 25(OH) vitamin D in skin or a decline in vitamin D absorption can result in the decline of muscle function [25]. Age-related insulin resistance causes an increase of fat infiltration into muscle and a decline in muscle strength [34]. Mitochondrial dysfunction in aging skeletal muscle causes oxidative damage and the decline of energy generation to maintain function properly [35].
The biological mechanisms underlying the association between sarcopenia and frailty are uncertain [36]. Any plausible explanations are that physical, motor, and cognitive functions are not causally related but are affected by common underlying pathophysiology [37]. Frailty, cognitive impairment, and sarcopenia share many common risk factors, such as immune or inflammatory response, oxidative stress, and hormonal dysregulation [38, 39]. In view of this, frailty, cognitive impairment, and sarcopenia may be highly interrelated [38, 40]. Inflammatory markers such as C-reactive protein and interleukin-6 concentrations are correlated negatively with muscle strength and physical performance [41, 42]. According to the definition of cognitive frailty, physical factors are the potential causes of cognitive impairment. In a study, high levels of these markers are associated with a 66% increase in cognitive impairment risk at 4-year follow-up in elders with metabolic syndrome [43]. Elevated oxidative stress [44], decreased sex steroid levels [45, 46], and insulin resistance [47, 48] are also involved in the association between physical and cognitive dysfunction.
2.3. The maintenance of muscle mass and function
The maintenance of normal muscle mass and function depends on the dynamic balance between positive and negative regulators of muscle growth. Muscle growth promoters include follustatin (FST), bone morphogenetic proteins (BMPs), brian-derived neurotrophic factor (BDNF), and irisin. Muscle growth suppressors contain myostatin, transforming growth factor beta (TGFβ), activins A and B, growth, and differentiation factor-11 and -15 [49, 50]. Age-related changes of these molecules, together with other factors, such as age-related diseases, chronic low-grade systemic inflammation, insulin resistance, endocrine aging, low physical activity, aging-related impairment of neuromuscular junction dysfunction, and contractile insufficiency because of skeletal muscle-specific troponin T leakage from sarcomere, result in imbalance between positive and negative regulators of muscle growth and sarcopenia development [49]. Muscle growth suppressors through the antibody-coupled, T-cell receptor/anaplastic lymphoma kinase 4,5 (ActR/Alk 4,5), or type I and II TGFβ receptor (TβRI and TβRII), phosphorylate mothers against decapentaplegic homolog 2/3 (SMAD 2/3), then combine SMAD 4 and inhibit the activation of an alternative pathway/mammalian target of rapamycin (Alt/mTOR) signal. TGFβ promotes SMAD3 binding to the promoters of both fibronectin type III domain containing 5 (FNDC5) and procaspase-activating compound 1α (PAC-1α), and suppresses the expression of irisin and PAC-1α [51].The elevated growth differentiation factor 11 (GDF11) increases the risk for age-related frailty and comorbidities [50]. Muscle growth promoters through their receptors phosphorylate SMAD 1/5/8 decrease the inhibition of Alt/mTOR signal and maintain muscle mass and strength. Insulin resistance due to aging, obesity, and diabetes results in the suppression of insulin/insulin-like growth factor-1/phosphatidyl Inositol 3-kinase/protein kinase B (IGF 1/PI3K/AKT)/mTOR, and muscle hypotrophy and dysfunction of metabolism; the less activated Alk fails to block the nuclear translocation of Foxo 3 to enhance the expression of autophagy-related genes and the consequent protein degradation [31, 52].
2.4. Sarcopenia accelerates systemic aging, frailty, and age-related diseases
Skeletal muscle influence systemic aging and lifespan by nutrient and stress sensors and myokines [53]. DNA damage and mutations are particularly prominent in aging skeletal muscle. Overexpression of phosphoenolpyruvate carboxykinase (PEPCK-C) and mitochondrial uncoupling proteins delays reproductive aging and decreases the incidence of several age-related diseases. Nutrient and stress sensors in sarcopenia include decreased sirturin 1 resulting from low nicotinamide adenine dinucleotide (NAD)+ synthesis and high NAD+ consumption and low adenosine monophosphate-dependent protein kinase (AMPK) activity, which results in the decline of the activity of peroxisome proliferator-activated receptor gamma coactivator-1a (PGC-1a) [54, 55]. The overexpression of AMPK and PGC-1a in muscle not only delays the age-related muscle deterioration but also slows the functional decline of other tissues, delay age-related metabolic defects, including systemic low-grade chronic inflammation, insulin resistance, increase in the stress resistance of the organism and extend lifespan. The other two nutrient sensors, insulin/insulin-like growth factor (IIS) and mTOR signaled nutrient abundance (high fat, amino acids, and sugar diet) and anabolic activity, are major accelerators of aging. mTOR inhibition by rapamycin or mTORC1 activity inhibition by genetical modification, and the downregulation of mTORC1/ribosomal protein S6 kinase beta-1 (S6K1) increases lifespan in mammals [55]. The decrease in regenerative capacity and skeletal muscle loss with age coincides with suppression of IIS pathways which is an attempt to promote longevity of the organism and survival within the tissue [56]. Age-related sarcopenia is associated with an increase in abdominal obesity, which refers to sarcopenic obesity [57]. Sarcopenic obesity leads to the infiltration of fat into the muscle and the accumulation of triglycerides within the cell, which impairs the function of the insulin receptor substrate causing insulin resistance, a lower lipid buffering capacity, and anabolic resistance in muscle [23, 58]. Sarcopenic obesity also results in cognitive impairment because of insulin resistance. In a cohort of 1570 older British men, compared with participants in the normal cognitive aging group, those elder men with severe cognitive impairment were more likely to be sarcopenic, with waist circumference >102 cm, BMI >30 kg/m2 and to be in the upper quintile of total fat mass, central fat mass, peripheral fat mass, and visceral fat level after age-adjusted multinomial logistic regressions [59]. In experiment animal mouse, obesity in combination with sarcopenia exacerbates blood-brain barrier disruption, neuroinflammation, and oxidative stress of hippocampus, which likely contribute to the remarkable cognitive decline [60]. Calorie restriction and exercise increase the concentrations of metabolic effectors NAD+ and AMP but reduce the concentrations of the hormonal effectors IIS and growth hormone. Meanwhile, these interventions also decrease the levels of glucose, amino acids, and lipids, recover downstream activity, such as DNA repair, mitochondrial biogenesis, and function, promote homeostasis, decrease frailty and comorbidities.
Beyond the profound influence on systemic aging and body metabolism, muscle secrete myokines, which act on muscles and other tissues, such as adipose, bones and brain in an autocrine, paracrine, and endocrine fashion [61]. The metabolites released from muscle and the interactions between muscle and nerve also participate in the systemic effects of muscle on the organism’s physiology. Exercise can activate PGC-1α/FNDC5 pathway, promote myokine irisin secretion, induce hippocampal BDNF release, and improve cognitive function [62].
3. From sarcopenia to frailty: the potential target molecules of intervention
The major causes of frailty include chronic diseases, such as congestive heart failure, diabetes, chronic obstructive pulmonary disease (COPD), anemia, polymyalgia rheumatic, and endocrine disorder; decreased nutrient intake because of anorexia resulting from social factors, decline in taste and smell, altered fundal compliance, enhanced release of cholecystokinin, increased leptin and cytokines, sarcopenia, and pain [63]. Treating the chronic diseases can reverse the loss of muscle mass and frailty, such as with angiotensin-converting enzyme inhibitors in some patients with congestive heart failure, both erythropoietin and darbepoietin-α in the individuals with anemia, and vitamin B12 supplementation in acrocytic anemia and related cognitive impairment. Lifestyle interventions play critical roles in the prevention of sarcopenia, frailty, and cognitive impairment. Physical exercise, particularly resistance exercise, can improve muscle mass and strength in the elderly [64, 65] and obese elderly [58]. Individuals with higher initial adiposity experience less improvement in both muscle strength and physical function [66]. Moreover, the addition of caloric restriction during resistance training improves mobility and does not compromise other functional adaptations to resistance training [66]. Resistance training also can increase circulating irisin [67] and improve cognitive performance [62]. In addition, physical exercise and caloric restriction can benefit age-related insulin resistance, reduced mitochondrial biogenesis, and failure of autophagy [68]. However, it is undesirable to use caloric restriction alone in sarcopenic elderly, which results in further loss of lean tissue mass. The oldest olds also with anabolic resistance and frailty find it difficult to perform resistance exercise to achieve benefit effects.
Dietary interventions including protein intake, antioxidants, and vitamin D fortification may benefit the conditions of sarcopenia and frailty. Protein supplies the amino acids, especially leucine, which may activate the signaling pathways required for muscle synthesis. Vitamin D deficiency is common in individuals with sarcopenia, frailty, and cognitive impairment. However, the effects of both protein supplementation and vitamin D intervention on muscle strength and physical performance have mixed results [69]. Although individuals with higher overall antioxidant status have better physical function, such as walking speed [70], antioxidant interventions might not attenuate, and even aggravate sarcopenia due to the health-promoting action of reactive oxygen spices [71].
There are no licensed treatments for sarcopenia and frailty. Pharmacological agents proposed and focused by investigators, with potential for treating sarcopenia include the myostatin signaling pathway and hormone replacement therapy (Table 1), currently are at various stages of development [72]. Myostatin, the family member of TGF-β, is a skeletal muscle-specific myokine. Myostain binding with activin type IIB receptor inhibits myoblast proliferation, muscle strength, and mass by negative regulation of mTOR signaling [73]. Myostatin inhibition by activin receptor trap or inhibitor and myostatin antibody might be useful agent for the treatment of human muscle degenerative diseases (Table 1) [72]. Testosterone supplementation is another major focus for drug discovery of sarcopenia. Testosterone could increase both muscle mass and strength in men but are linked to adverse cardiovascular events with short durations of therapy [74, 75]. In order to decrease the side effects of testosterone, the selective androgen receptor molecules, including steroids and nonsteroids, have been developed, and some are at phase 3 (Table 1). Tirasemtiv is a fast skeletal troponin activator that sensitizes the sarcomere to calcium and amplifies the function of muscle in neuromuscular diseases, such as Amyotrophic Lateral Sclerosis and myasthenia gravis (Table 1) [76, 77].
Mechanism of action
Drug name
Drug developer
Indication sought
Study phase
I. Myostatin antagonists
Activin receptor trap
ACE-031
Acceleron
Duchenne muscular dystrophy
Phase 3 (trial terminated early)
Myostatin antibody
REGN-1033
Regeneron/Sanofi
Sarcopenia
Phase 2
LY-2495655
Eli Lilly
Hip arthroplasty Elderly Fallers Cancer cachexia
Phase 2
PF-06252616
Pfizer
Inclusion body myositis
Phase 1
Activin receptor inhibitor
Bimagrumab (BMY338)
Novartis
Sarcopenia Hip fracture Cancer and COPD cachexia
Phases 2 and 3 Phase 2
II. Selective androgen receptor modulators
Enobasarm (ostarine)
GTx
Cancer cachexia
Phase 3 (did not meet primary endpoint)
III. Skeletal troponin activators
Tirasemtiv CK-2017357
Cytokinetics
Amyotrophic lateral sclerosis myasthenia gravis
Phases 2 and 3
Table 1.
Pharmacological agents in development with potential for treating sarcopenia [72].
Age is the greatest risk factor for nearly every major cause of mortality in developed nations [78] and the profound effect of aging on sarcopenia, frailty, and cognitive impairment is often overlooked. A number of aging-associated molecular signals might be the potential target in the prevention and treatment of sarcopenia, frailty, and cognitive impairment. Genetic or pharmacological regulation of NAD+/Sirt1, sestrins/AMPK/PGC1α, IGF-1/Akt/mTOR, TGF-β, myostatin, activins, GDFs /SMAD2/3, BMPs/SMAD1/5/8 signal molecules, myokine irisin and FGF21, the antagonist of myokine myostatin propeptide follistatin or follistatin-like 3, and urocortins can not only improve muscle mass and/or function but also delay frailty and age-related diseases [31, 54, 68]. Besides dietary restriction and exercise, geroscience interventions with translational potential include mTOR inhibitors, metformin and acarbose, NAD precursors and sirtuin activators, modifiers of senescence and telomere dysfunction, hormonal and circulating factors, and mitochondrial-targeted therapeutics [78]. Phytochemicals obviously are ideal geroscience interventions with translational potential. They not only have multiple target molecules in many aging-related signalling pathways, such as sestrins/AMPK/PGC1α, IGF-1/Akt/mTOR, against chronic inflammation and oxidative stress but also have systemic influence with low side effects, including skeletal muscle and other domains of frailty [79, 80].
4. Conclusion and perspective
Sarcopenia is one of the important causes of physical frailty. Frailty contains different phenotypes, such as physical frailty and cognitive frailty or multiple domains in frailty index. Skeletal muscle influences body metabolism, systemic aging, accelerates physical frailty, cognitive impairment, and decrease healthy lifespan. Individuals with primary sarcopenia have an increase in the risk for frailty, cognitive impairment, and age-related diseases. Aging might be the common mechanism of sarcopenia, frailty, and cognitive impairment. Cognitive frailty is an important target of the prevention for both physical and cognitive disability [81]. Although some pharmacological agents are registered in different phases of clinical trials for sarcopenia intervention, no drug is really used for the clinical treatment of sarcopenia. Phytochemicals have effects on multiple targets of aging-related signaling pathways, and other targeted aging molecules, such as mTOR inhibitors, metformin and acarbose, NAD precursors, and sirtuin activators [78, 82], have preventive and therapeutic perspectives on sarcopenia, frailty, and age-related diseases.
Acknowledgments
This work was supported by grants from the Shanghai Hospital Development Center (No. SHDC12014221), Shanghai Municipal Commission of Health and Family Planning, Key developing disciplines (2015ZB0501).
\n',keywords:"sarcopenia, physical frailty, cognitive frailty, aging",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/55942.pdf",chapterXML:"https://mts.intechopen.com/source/xml/55942.xml",downloadPdfUrl:"/chapter/pdf-download/55942",previewPdfUrl:"/chapter/pdf-preview/55942",totalDownloads:733,totalViews:481,totalCrossrefCites:0,totalDimensionsCites:2,hasAltmetrics:0,dateSubmitted:"September 15th 2016",dateReviewed:"May 8th 2017",datePrePublished:null,datePublished:"August 30th 2017",readingETA:"0",abstract:"Skeletal muscle is not only an endocrine organ but also one of core components of muscloskeletal system. Sarcopenia refers to a decline in the skeletal muscle mass and function. The former involves the size and number of changes in two types of myofibers, lower satellite cell density, and regeneration ability. The latter shows a loss of muscle strength. Frailty is a geriatric syndrome with multisystem impairment associated with increased vulnerability to stressors. Sarcopenia increases the risk of frailty and may be one of the major causes of physical frailty phenotype. Sarcopenia is also potentially associated with cognitive frailty phenotype. Aging might be the common underlying pathophysiology of sarcopenia and frailty. Therefore, there are some potential target molecules in aging-related signaling pathways that might be associated with sarcopenia and frailty. Nevertheless, sarcopenia can mediate metabolism and promote accelerate systemic aging, frailty, and age-related diseases by myokines in an endocrine manner. Lifestyle interventions (resistance exercise and dietary restriction) of gerontoscience are effective in the prevention of sarcopenia. Some pharmacological agents are registered in different phases of clinical trials for sarcopenia intervention. Phytochemicals, mTOR inhibitors, metformin and acarbose, NAD precursors, and sirtuin activators demonstrated that multiple target antiaging effects might also have preventive and therapeutic perspectives on sarcopenia and frailty.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/55942",risUrl:"/chapter/ris/55942",book:{slug:"frailty-and-sarcopenia-onset-development-and-clinical-challenges"},signatures:"Zhuowei Yu, Qingwei Ruan, Grazia D’Onofrio and Antonio Greco",authors:[{id:"184080",title:"Dr.",name:"Grazia",middleName:null,surname:"D’Onofrio",fullName:"Grazia D’Onofrio",slug:"grazia-d'onofrio",email:"graziadonofrio@libero.it",position:null,institution:{name:"Casa Sollievo della Sofferenza",institutionURL:null,country:{name:"Italy"}}},{id:"195813",title:"Prof.",name:"Qingwei",middleName:null,surname:"Ruan",fullName:"Qingwei Ruan",slug:"qingwei-ruan",email:"13661717346@163.com",position:null,institution:{name:"Fudan University",institutionURL:null,country:{name:"China"}}},{id:"204892",title:"Prof.",name:"Zhuowei",middleName:null,surname:"Yu",fullName:"Zhuowei Yu",slug:"zhuowei-yu",email:"hdyuzhuowei@163.com",position:null,institution:null},{id:"204898",title:"Prof.",name:"Antonio",middleName:null,surname:"Greco",fullName:"Antonio Greco",slug:"antonio-greco",email:"antoniogreco4@yahoo.it",position:null,institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. From Sarcopenia to frailty: the pathophysiological basis",level:"1"},{id:"sec_2_2",title:"2.1. From sarcopenia to physical and cognitive frailty: the epidemiological evidence",level:"2"},{id:"sec_3_2",title:"2.2. Aging promotes sarcopenia and frailty",level:"2"},{id:"sec_4_2",title:"2.3. The maintenance of muscle mass and function",level:"2"},{id:"sec_5_2",title:"2.4. Sarcopenia accelerates systemic aging, frailty, and age-related diseases",level:"2"},{id:"sec_7",title:"3. From sarcopenia to frailty: the potential target molecules of intervention",level:"1"},{id:"sec_8",title:"4. Conclusion and perspective",level:"1"},{id:"sec_9",title:"Acknowledgments",level:"1"}],chapterReferences:[{id:"B1",body:'Fried LP, Tangen CM, Walston J, et al. Frailty in older adults evidence for a phenotype. The Journals of Gerontology. 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Shanghai Institute of Geriatrics and Gerontology, Shanghai Key Laboratory of Clinical Geriatrics, Huadong Hospital, Shanghai, China
Research Center of Aging and Medicine, Shanghai Medical College, Fudan University, Shanghai, China
Department of Medical Sciences, Geriatric Unit & Laboratory of Gerontology and Geriatrics, IRCCS “Casa Sollievo della Sofferenza”, San Giovanni Rotondo, Foggia, Italy
Department of Medical Sciences, Geriatric Unit & Laboratory of Gerontology and Geriatrics, IRCCS “Casa Sollievo della Sofferenza”, San Giovanni Rotondo, Foggia, Italy
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Takahashi",authors:[{id:"78952",title:"Dr.",name:"Sumihisa",middleName:null,surname:"Orita",fullName:"Sumihisa Orita",slug:"sumihisa-orita"},{id:"96524",title:"Dr.",name:"Seiji",middleName:null,surname:"Ohtori",fullName:"Seiji Ohtori",slug:"seiji-ohtori"},{id:"96525",title:"Prof.",name:"Kazuhisa",middleName:null,surname:"Takahashi",fullName:"Kazuhisa Takahashi",slug:"kazuhisa-takahashi"},{id:"126366",title:"Dr.",name:"Gen",middleName:null,surname:"Inoue",fullName:"Gen Inoue",slug:"gen-inoue"}]},{id:"29561",title:"Pharmacological Treatment of Osteoporosis",slug:"pharmacological-treatment-of-osteoporosis",signatures:"Jorge Malouf-Sierra and Roberto Güerri-Fernández",authors:[{id:"83037",title:"Dr.",name:"Jorge",middleName:null,surname:"Malouf Sierra",fullName:"Jorge Malouf Sierra",slug:"jorge-malouf-sierra"},{id:"118982",title:"Dr.",name:"Robert",middleName:null,surname:"Güerri-Fernández",fullName:"Robert Güerri-Fernández",slug:"robert-guerri-fernandez"}]},{id:"29562",title:"The Role of Hormone Replacement Therapy (HRT) and Tibolone in the Prevention and Treatment of Postmenopausal Osteoporosis",slug:"the-role-of-hormone-replacement-therapy-hrt-and-tibolone-in-the-prevention-and-treatment-of-postmeno",signatures:"Marta Lamarca",authors:[{id:"81148",title:"Dr.",name:"Marta",middleName:null,surname:"Lamarca",fullName:"Marta Lamarca",slug:"marta-lamarca"}]},{id:"29563",title:"Osteonecrosis of the Jaw Involving Bisphosphonate Treatment for Osteoporosis",slug:"osteonecrosis-of-the-jaw-involving-bisphosphonate-treatment-for-osteoporosis",signatures:"Maria Panaś, Małgorzata Zaleska and Tomasz Kaczmarzyk",authors:[{id:"85541",title:"Dr",name:"Maria",middleName:null,surname:"Panaś",fullName:"Maria Panaś",slug:"maria-panas"},{id:"122594",title:"Dr.",name:"Małgorzata",middleName:null,surname:"Zaleska",fullName:"Małgorzata Zaleska",slug:"malgorzata-zaleska"},{id:"122595",title:"Dr.",name:"Tomasz",middleName:null,surname:"Kaczmarzyk",fullName:"Tomasz Kaczmarzyk",slug:"tomasz-kaczmarzyk"}]},{id:"29564",title:"Balloon Kyphoplasty for Osteoporosis: Technical Notes",slug:"balloon-kyphoplasty-for-osteoporosis-technical-notes",signatures:"Antoine Nachanakian, Antonios El Helou, Sami Salem and Moussa Alaywan",authors:[{id:"116842",title:"Prof.",name:"Antoine",middleName:null,surname:"Nachanakian",fullName:"Antoine Nachanakian",slug:"antoine-nachanakian"},{id:"117443",title:"Dr.",name:"Antonios",middleName:"Georges",surname:"El Helou",fullName:"Antonios El Helou",slug:"antonios-el-helou"},{id:"117444",title:"Dr.",name:"Sami",middleName:null,surname:"Salem",fullName:"Sami Salem",slug:"sami-salem"},{id:"117445",title:"Dr.",name:"Moussa",middleName:null,surname:"Alaywan",fullName:"Moussa Alaywan",slug:"moussa-alaywan"}]},{id:"29565",title:"Minimally Invasive Treatment of Vertebral Body Fractures",slug:"minimally-invasive-treatment-of-vertebral-body-fractures",signatures:"Pasquale De Negri and Tiziana Tirri",authors:[{id:"75553",title:"Dr.",name:"Pasquale",middleName:null,surname:"De Negri",fullName:"Pasquale De Negri",slug:"pasquale-de-negri"},{id:"85148",title:"Dr.",name:"Tiziana",middleName:null,surname:"Tirri",fullName:"Tiziana Tirri",slug:"tiziana-tirri"}]},{id:"29566",title:"Osteoporosis: A Look at the Future",slug:"osteoporosis-a-look-at-the-future",signatures:"Iliyan Kolev, Lyudmila Ivanova, Leni Markova, Anelia Dimitrova, Cyril Popov and Margarita D. Apostolova",authors:[{id:"75527",title:"Dr.",name:"Margarita",middleName:"Dimitrova",surname:"Apostolova",fullName:"Margarita Apostolova",slug:"margarita-apostolova"},{id:"86282",title:"MSc.",name:"Iliyan",middleName:null,surname:"Kolev",fullName:"Iliyan Kolev",slug:"iliyan-kolev"},{id:"86283",title:"MSc.",name:"Lyudmila",middleName:null,surname:"Ivanova",fullName:"Lyudmila Ivanova",slug:"lyudmila-ivanova"},{id:"86284",title:"Mrs.",name:"Leni",middleName:null,surname:"Markova",fullName:"Leni Markova",slug:"leni-markova"},{id:"86286",title:"Prof.",name:"Anelia",middleName:"Aleksandrova",surname:"Dimitrova",fullName:"Anelia Dimitrova",slug:"anelia-dimitrova"},{id:"86289",title:"Prof.",name:"Cyril",middleName:null,surname:"Popov",fullName:"Cyril Popov",slug:"cyril-popov"}]},{id:"29567",title:"Simulating Bone Atrophy and Its Effects on the Structure and Stability of the Trabecular Bone",slug:"simulating-bone-atrophy-and-its-effects-on-the-structure-and-stability-of-the-trabecular-bone",signatures:"Christoph Räth, Irina Sidorenko, Roberto Monetti, Jan Bauer, Thomas Baum, Maiko Matsuura, Philippe Zysset and Felix Eckstein",authors:[{id:"56283",title:"Dr.",name:"Christoph",middleName:null,surname:"Räth",fullName:"Christoph Räth",slug:"christoph-rath"}]},{id:"29568",title:"Role of Phytoestrogen Ferutinin in Preventing/Recovering Bone Loss: Results from Experimental Ovariectomized Rat Models",slug:"role-of-phytoestrogen-ferutinin-in-preventing-recovering-bone-loss-results-from-experimental-ovariec",signatures:"Carla Palumbo, Francesco Cavani, Laura Bertoni and Marzia Ferretti",authors:[{id:"75816",title:"Prof.",name:"Carla",middleName:null,surname:"Palumbo",fullName:"Carla Palumbo",slug:"carla-palumbo"},{id:"84964",title:"Prof.",name:"Marzia",middleName:null,surname:"Ferretti",fullName:"Marzia Ferretti",slug:"marzia-ferretti"},{id:"84968",title:"Dr.",name:"Francesco",middleName:null,surname:"Cavani",fullName:"Francesco Cavani",slug:"francesco-cavani"},{id:"84970",title:"Dr.",name:"Laura",middleName:null,surname:"Bertoni",fullName:"Laura Bertoni",slug:"laura-bertoni"}]},{id:"29569",title:"The Phytoestrogens, Calcitonin and Thyroid Hormones: Effects on Bone Tissue",slug:"the-phytoestrogens-calcitonin-and-thyroid-hormones-effects-on-bone-tissue",signatures:"Branko Filipović and Branka Šošić-Jurjević",authors:[{id:"44958",title:"Dr.",name:"Branko",middleName:null,surname:"Filipovic",fullName:"Branko Filipovic",slug:"branko-filipovic"},{id:"85513",title:"Dr.",name:"Branka",middleName:null,surname:"Sosic-Jurjevic",fullName:"Branka Sosic-Jurjevic",slug:"branka-sosic-jurjevic"}]},{id:"29570",title:"Nutrition for Enhancing Bone Volume in Mice",slug:"nutrition-for-enhancing-bone-volume-in-mice",signatures:"Junji Ohtani, Fujita Tadashi, R.A. Marquez Hernandez, Toshitsugu Kawata, Masato Kaku, Masahide Motokawa and Kazuo Tanne",authors:[{id:"81412",title:"Dr.",name:"Junji",middleName:null,surname:"Ohtani",fullName:"Junji Ohtani",slug:"junji-ohtani"}]},{id:"29571",title:"Osteoporosis and Bone Regeneration",slug:"osteoporosis-and-bone-regeneration",signatures:"Shinji Kuroda, Kanako Noritake and Shohei Kasugai",authors:[{id:"61656",title:"Prof.",name:"Shohei",middleName:null,surname:"Kasugai",fullName:"Shohei Kasugai",slug:"shohei-kasugai"},{id:"84104",title:"Dr.",name:"Shinji",middleName:null,surname:"Kuroda",fullName:"Shinji Kuroda",slug:"shinji-kuroda"},{id:"90335",title:"Dr.",name:"Kanako",middleName:null,surname:"Noritake",fullName:"Kanako Noritake",slug:"kanako-noritake"}]},{id:"29572",title:"Lactoferrin – A Potential Anabolic Intervention in Osteoporosis",slug:"lactoferrin-a-potential-anabolic-intervention-in-osteoporosis",signatures:"Dorit Naot, Kate Palmano and Jillian Cornish",authors:[{id:"78754",title:"Prof.",name:"Jillian",middleName:null,surname:"Cornish",fullName:"Jillian Cornish",slug:"jillian-cornish"},{id:"84689",title:"Dr.",name:"Dorit",middleName:null,surname:"Naot",fullName:"Dorit Naot",slug:"dorit-naot"},{id:"84704",title:"Dr.",name:"Kate",middleName:null,surname:"Palmano",fullName:"Kate Palmano",slug:"kate-palmano"}]},{id:"29573",title:"How Dentistry Can Help Fight Osteoporosis",slug:"how-dentistry-can-help-fight-osteoporosis",signatures:"Plauto Christopher Aranha Watanabe, Marlivia Gonçalves de Carvalho Watanabe and Rodrigo Tiossi",authors:[{id:"76171",title:"Prof.",name:"Plauto C. A.",middleName:null,surname:"Watanabe",fullName:"Plauto C. A. Watanabe",slug:"plauto-c.-a.-watanabe"}]},{id:"29574",title:"Effect of Bisphosphonates on Root Growth and on Chlorophyll Formation in Arabidopsis thaliana Seedlings",slug:"effect-of-bisphosphonates-on-root-growth-and-on-chlorophyll-formation-in-arabidopsis-thaliana-seedli",signatures:"Ana I. Manzano, F. Javier Medina, Francisco J. Pérez-Zuñiga, Maria A. Günther Sillero and Antonio Sillero",authors:[{id:"81573",title:"Prof.",name:"Antonio",middleName:null,surname:"Sillero",fullName:"Antonio Sillero",slug:"antonio-sillero"}]}]}]},onlineFirst:{chapter:{type:"chapter",id:"64249",title:"A Novel P53/POMC/Gas/SASH1 Autoregulatory Feedback Loop and Pathologic Hyperpigmentation",doi:"10.5772/intechopen.81567",slug:"a-novel-p53-pomc-gas-sash1-autoregulatory-feedback-loop-and-pathologic-hyperpigmentation",body:'\n
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1. Introduction
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The skin pigmentation is formed by the synthesis of melanin in the melanocytes. Melanocyte is a kind of epithelial cells mainly locating basal cell layers of epidermis, and a few number of melanocytes are located in mucosa. Pigment granules constituted with melanin can distribute and transport to neighboring keratinocytes [1]. Mutations in melanocortin-1-receptor (MC1R) are pivotal for human skin’s tanning and pigmentation. MC1R belongs to a G-protein-coupled receptor (GPCR) that is expressed in epidermal melanocytes in a preferential manner [2]. α-Melanocyte-stimulating hormone (α-MSH), the GPCR’s ligand, is a propigmentation hormone which is generated and secreted by both keratinocytes and melanocytes in the skin. After UV irradiation, α-MSH can activate GPCR. Pro-opiomelanocortin (POMC) is a multicomponent precursor for α-MSH (melanotropic), ACTH (adrenocorticotropic), and the opioid peptide β-endorphin, and α-MSH and other bioactive peptides are the cleavage products of POMC [2]. Normal synthesis of α-MSH and ACTH is extremely important to constitutive human pigmentation and the cutaneous response to UV [2].
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In melanocytes, the amount and type of pigment production are regulated by MC1R. So MC1R is an important determiner of skin phototype, sensitivity to UV radiation-induced damage, and skin cancer risk [3]. The heterotrimeric G proteins consist of α, β, and γ subunits. Upon ligand binding, a signal is transmitted by GPCRs to heterotrimeric G proteins, which results in the separation of the α subunit from the Gβγ subunit of G proteins. ATP is catalyzed to be directly transformed to cAMP by the G proteins of the Gαs class and cAMP is in charge of melanogenesis including the sensitization of tyrosinase in melanin biosynthesis upon being activated by ligands such as α-MSH [4].
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p53 is not only a transcriptional factor but also a tumor-suppressor protein, which is documented to directly sensitize the transcription of a lot of genes including those that control cell cycle, apoptosis, and others. POMC/MSH inducement by UV irradiation in skin is directly regulated by p53 and POMC promoter is stimulated in response to UV irradiation. p53 involves in UV-independent pathologic pigmentation and could imitate the tanning response [1]. Dipyrimidine C to T substitutions including CC to TT frameshift mutations in the p53 gene can be uniquely induced by UV in the skin of UV-irradiated mice months before tumor development [5]. In addition, p53 has been demonstrated to be necessary to the presentation of “sunburn cells,” which are a sign of sunburns [5].
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DUH characterized by extensively mottled pigmentation is a heterogeneous disorder, which was first diagnosed by two Japanese researchers in two generations of two pedigrees for about 80 years [6, 7]. Similar Chinese DUH pedigrees with dyschromatosis symmetrica hereditaria (DSH) with autosomal dominant DUH had been reported by us in 2003 [8] and diagnosed as DUH rather than DSH afterward. Although novel mutations of SASH1 have been identified to be associated with dyschromatosis universalis hereditaria [9], less pathogenesis of DUH has not been investigated. The pathogenesis of DUH remain unclear and indefinite for 80 years [7].
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SASH1, a previously described novel family of putative adapter and scaffold proteins transmitting signals from the ligand to the receptor, was first showed to be a candidate tumor-suppressor gene in breast cancer and colon carcinoma [10, 11, 12]. Our previous study demonstrates that SASH1 interacts with Gαs, the downstream player of α-MSH/MC1R signaling pathway [13]. Our previous report indicated that in the several affected DUH individuals, hyperpigmented macules became more obvious after strong UV irradiation particularly in summer [8], but no further investigations was performed to identify the reasons of photosensitivity [14]. The significance of expression of p53/POMC/α-MSH in UV-photopigmentation response and UV-independent hyperpigmentation has been explained [1]. However, few investigations were performed to reveal that the mutations in SASH1 gene are related to hyperpigmentation and how these mutations result in hyperpigmentation phenotype.
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In a word, we assume that a novel p53/POMC/α-MSH/Gαs that SASH1 involves in regulating UV-photopigmentation response and pathological hyperpigmentation phenotype.
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2. Materials and methods
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2.1 DUH pathologic gene sequencing and SASH1 mutation analysis
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Two Chinese pedigrees recruited from the Henan and Yunnan provinces of China and one American pedigree with typical features of DUH were involved in this study. Three DUH pedigrees with an autosomal dominant inheritance pattern were diagnosed by skilled clinical dermatologists. The small American pedigree only offered peripheral blood samples of the affected individuals for investigations. This study was recognized by the ethical review committees from the appropriate institutions. Genotyping was implemented, and the two-point LOD score was counted as our previous description [8]. In total, 50 family members and 500 normal individuals (controls) involved in the research were provided with informed consent and specimens of peripheral blood DNA were acquired from all obtainable family members. PCR and sequencing were executed as our previous description [8]. ABI BigDye Terminator Cycle Sequencing Kit (Applied Biosystems, CA) was used to perform the sequencing on an ABI PRISM 3130 DNA Analyzer (Applied Biosystems) and sequence analysis software, version 3.4.1 (Applied Biosystems) were used to analyze the data. Sequencher 4.10.1 (Gene Codes Corp.) was used to compare the sequence data with SASH1 reference sequence (GenBank NM_015278.30). Nucleotide numbering reflects complementary DNA (cDNA) numbering, with +1 corresponding to the A of the ATG translation initiation codon in the reference sequence [8].
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2.2 Constructing expression vectors of SASH1, Gαs, POMC, and p53
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Wild-type and mutant SASH1-PEGFP-C3 and wild-type and mutant SASH1-PBABE-Flag-puro were constructed according to the protocol of our previous study [13]. To generate the p53-HA-Pcna3.0, POMC-myc-Pcdna3.0 and Gαs-Pegfp-C3 vectors, high fidelity DNA polymerase (Phusion Hot Start High Fidelity Polymerase from New England Biolabs, Inc. or GXL Polymerase from Takara) and the primers indicated in Table 1 were used to amplify the bacteria (obtained from Han Jiahuai Lab, Xiamen University, Xiamen, China) containing the vector of full-length CDS sequences of and Gαs, p53 and POMC. Mammalian expression vector (Invitrogen) via the relative restriction sites and sequenced.
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Name of primers or probes
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Sequences (5′–3′)
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Gαs forward primer (SalI site included)
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ACGCGTCGACATGGGCTGCCTCGGGAAC
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Gαs reverse primer (XhoI site included)
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CCGCTCGAGTTAGAGCAGCTCGTACTGACG
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p53 forward primer (BamHI site included)
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CGCGGATCCGCCACCACCATGGAGGAGCCGCAGTCAGATCCTA
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p53 reverse primer (XhoI site included)
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CCGCT CGAG TCAGTCTGAG TCAGGCCCTTCTGT
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POMC forward primer (BamHI site included)
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CGCGGATCCATGCCGAGATCGTGCTGC
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POMC reverse primer (XhoI site included)
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CCCAAGCTTTCACTCGCCCTTCTTGTAGGCGTTCTTGAT
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SASH1 probe 1#
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GCCCAAGCTTTCACACTTGTTT
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SASH1 probe 2#
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CCAAGACTTGCTAGAAGGAACGAGTCG
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SASH1 probe 3#
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CGTGGCCACCTAG ACCCGAGGTG
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Table 1.
Sequences of primers or probes used in gene cloning and EMSA in this study.
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2.3 Culture of cell and vector transfection
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SK-MEL-28, HEK-293T, and A375 cells were cultured according to our previous description [15]. Normal human epithelial melanocytes (NHEMs, C-12402, PromoCell, Germany) were maintained in M2 medium. Lipofectamine 2000 (11668-027, Invitrogen) as previously described [15, 16] or Entranster-D (18668-01, Engreen Biosystem Co., Ltd.) or polyethyleneimine (PEI) prepared by ourselves were, respectively, used for the transfection of SK-MEL-28, A375, B16, and HEK-293T cells. The transfected A375 and SK-MEL-28 cells were screened with 1.5 μg/ml puromycin or 2.0 μg/ml G418 to construct stable cell lines. Wild-type and mutant SASH1-pEGFP-C3 or co-transfected with wild-type SASH1-Pbabe-Flag-puro and Gαs-Pegfp-C3 vectors were transiently introduced into HEK-293T cells for immunoprecipitation experiments. p53-HA-Pcdna3.0, POMC-myc-Pcdna3.0, Gαs-Pegfp-C3, and wild-type SASH1-pEGFP-C3 according to pairwise combination were introduced into NHEMs and HEK-293 or HEK-293T cells to detect the expression of exogenous p53, POMC, Gαs, and SASH1 using PEI or PromoFectin (PK-CT-2000-MAC-1, PromoCell).
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Gαs-GFP, HA-p53, myc-POMC, and GFP-SASH1 recombined vector were introduced into HEK-293T cells. 24 h later, Entranster™-R transfection reagent (18668-06, Engreen Biosystem Co., Ltd) was used to transfect Gαs- and POMC-specific siRNAs synthesized by Shanghai GenePharma Co., Ltd. (Shanghai, China) to silence the expression of exogenous Gαs, p53, and SASH1 in the transfected HEK-293T cells. The sense/antisense sequences of each siRNA for Gαs, POMC are documented in Table 2.
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Gene name
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Forward primer (5′–3′)
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Reverse primer (5′–3′)
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SASH1
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CGGGAAACGTCAAGTCGGA
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ATCTCCTTTCTTGAGCTTGAG
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TYRP1
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CACAGGCACAGGTACCACCTC
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CTGAACTACCCTAGGTCTTCGTT
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Pmel17
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AAGGTCCAGATGCCAGCTCAA
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CTTTCACGGCTCTAGGACGTC
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Rab 27a
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AACTAGTGCTGCCAATGGGACA
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TTTGATCGCACCACTCCTTC
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Gαs
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GTCCTTGCTGGGAAATCG
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CGCAGGTGAAATGAGGGTAG
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p53
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CCACCATCCACTACAACTACAT
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TCCCAGCACAGGCACAAA
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POMC
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AGTTCAAGAGGGAGCTGACTGG
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CATGAAACCGCCGTAGCG
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GAPDH
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CACCCACTCCTCCACC TTTG
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ACCACCCTGTTGCT GTAGCC
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Gαs siRNA 1
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GAGGACUACUUUCCAGAAUTT
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AUUCUGGAAAGUAGUCCUCTT
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Gαs siRNA 2
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GCAGCUACAACAUGGUCAUTT
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AUGACCAUGUUGUAGCUGCTT
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POMC siRNA1
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ACCUCACCACGGAAAGCAATT
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UUGCUUUCCGUGGUGAGGUTT
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POMC siRNA2
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AGUACGUCAUGGGCCACUUTT
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AAGUGGCCCAUGACGUACUTT
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GAPDH
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GUAUGACAACAGCCUCAAGTT
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CUUGAGG CUGUUGUCAUACTT
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Negative control
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UUCUUCGAACGUGUCACGUTT
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ACGUGACACGUUCGG AGAATT
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Table 2.
Primers used for site directed mutagenesis, real time RT-PCR and RNAi.
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2.4 Pull-down experiments and nanoflow LC-MS/MS and bioinformatic assays
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Procedure of the pull-down assay, LC-MS/MS analyses, database search, and bioinformatic analyses for functional classification are mainly as performed as our previous description [13].
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2.5 Immunoprecipitation and westernblotting
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Transfected HEK-293T cells or HEK-293 cells or NHEMs with ectopic exogenous genes were washed in a gentle way for three times with PBS and lysed in IP-western blot lysis buffer (P0013, Beyond Time BioScience and Technology Company) in the presence of a complete protease inhibitor cocktail, 1 μM sodium orthovanadate, and 1 mM sodium fluoride per 10 cm dish on ice for 20 min to acquire lysisprotein. Cell lysates were centrifuged for 10 min at 12,000 rpm at 4°C. 600 μl of supernatants of cell lysates were pre-cleaned with Protein A/G PLUS-Agarose (Santa Cruz Biotechnology, Inc.) for 1 h. GFP-Tag (7G9) mouse mAb (Shanghai Abmart, Inc.) or DYKDDDDK-Flag-Tag mouse mAb (Shanghai Abmart) or HA-Tag mouse mAb (Shanghai Genomics) was used to immunoprecipitate the corresponding proteins at 4°C for 2 h. Then, the cell lysates were mixed with 20 μl of Protein A/G PLUS-Agarose (Santa Cruz Biotechnology, Inc.) at 4°C for 10 h for co-immunoprecipitation or immunoprecipitation analyses. Finally, immunoprecipitates were washed for three times with PBS and subjected to western blotting. GFP-Tag mouse Ab, Flag-tag mouse mAb, DYKDDDDK-Flag mouse mAb, GAPDH mouse mAb and anti-β-tubulin mouse mAb (Shanghai Abmart, Inc.), anti-Gαs rabbit polyclonal Ab (Gene Tex, Inc.), myc-tag mAb and HA-tag mouse mAb (Shanghai Genomics), SASH1 Rabbit mAb (Bethyl Laboratories, Inc.), TYRP1 (TA99) mouse mAb and melanoma gp100 Rabbit mAb (Abcam), Rab 27a mouse mAb (Abnova) were used for immunoblotting assay as previously described [17, 18].
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2.6 Immunohistochemical analyses and immunofluorescence staining and melanin staining
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2.6.1 Immunohistochemistry
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All participating patients in this study were given the written informed consent regarding tissue and data use for scientific purposes. Epithelial tissues from affected individuals with the Y551D SASH1 mutation from pedigree I were fixed and embedded in paraffin. Paraffin sections (5 μm) were baked at 56°C for 3 h, and then deparaffinized and rehydrated using xylene and an ethanol gradient. SASH1 monoclonal antibody, rabbit anti-ACTH antibody, MiTF polyclonal antibody, the antibodies of melanogenesis related molecules including HMB45, TYRP1, and Rab 27a and p53 monoclonal antibody was used to bind the corresponding proteins on paraffin sections, respectively. Finally, counterstaining of hematoxylin was performed and the sections were photographed under the positive position microscope BX51.
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2.6.2 Immunofluorescence (IF) and confocal microscopy detection
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A375 stable cells with ectopic wild-type or mutant SASH1 in 6-well chamber slides were analyzed with indirect immunofluorescence analysis. SASH1 rabbit mAb (Betheyl Laboratories, Inc.) and DYKDDDDK-Flag mouse mAb (Shanghai Genomics, China) were used to assess SASH1 localization and expression, as described previously [13].
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2.6.3 Melanin staining
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The melanin staining of paraffin sections obtained from epithelial tissues were performed as our previous descriptions and observed under a light microscope [18].
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2.7 Quantitative RT-PCR
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TRIzol reagent (Invitrogen) was used to isolate the total RNA from the different groups of SK-MEL-28 cells. Reverse transcription was performed according to the manufacturer’s protocol for the PrimeScript™ RT Reagent Kit (DRR037A, TaKaRa) for qRT-PCR. The sense and antisense primer sequences for SASH1, TYRP1, Pmel17, Rab27a, Gαs, POMC, and GAPDH are showed in Table 2. The PCR products were identified by agarose gel electrophoresis. The Applied Biosystems 7500 System was applied to detect the expression of corresponding genes with SYBR Premix Ex Taq™ (DRR041A, TaKaRa). The quantity of each mRNA was normalized to that of GAPDH mRNA.
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2.8 UV irradiation
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Human foreskin tissues from a 14 year-old boy were irradiated for enough time under a ultraviolet phototherapy instrument (NBUVB SS-05, Sigma) to reach the expected UV intensity. The irradiated tissues were fixed in 10% formalin and embedded in paraffin for immunohistochemistry analyses. We conformed to the guidelines of the World Medical Assembly (Declaration of Helsinki) to acquire the human foreskin tissues. In vitro UV experiments were mainly referred to the protocol of our institute [19]. HEK-293T cells and NHEMs transiently with ectopic myc-POMC were subcultured to approximately 70–80% confluence and were irradiated with 100 mJ/cm2 UVC delivered via a HL-2000 HybriLinker with a 254 nm wavelength and followed by the indicated recovery time. Finally, immunobloting was performed to identify the corresponding proteins’ levels.
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2.9 Electrophoretic mobility shift assay
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Three probes binding with/without biotin targeting the promoter sequence of SASH1 gene were synthesized. The sequences of probes were as indicated in Table 1. Electrophoretic mobility shift assay was performed as described as the protocol provided with LightShift® Chemiluminescent EMSA (20148, Thermo Scientific, Pierce Biotechnology) to detect the bindings of SASH1 with p53 [18].
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2.10 Statistical analyses
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The data are indicated as mean ± standard error of the mean (SEM)s. The homogeneity of variance test was first used to analyze the variance homogeneity of data and the data were analyzed the change of variable test. Statistical significance was determined by a one-factor analysis of variance (ANOVA) using LSD on SPSS version 16.0 to produce the required p-values. Cartograms were plotted with GraphPad Prism 5.
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3. Results
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3.1 Mutations in SASH1 gene in the DUH-affected individuals result in up-regulated SASH1 in vitro and in vivo
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The gene that is responsible for DUH had been localized to chromosome 6q24.2-q25.2. The 10.2 Mb region on chromosome 6 (6q24.2-q25.2) containing more than 50 candidate genes is flanked by the markers D6S1703 and D6S1708 [8]. Direct sequencing of the PCR products of exons amplified from genomic DNA of affected, unaffected, and control individuals was performed to screen the selected genes in this region for possible pathological mutations. 50 candidate genes were sequenced. Finally, in the probands in each of the two nonconsanguineous Chinese DUH-affected pedigrees (families I and II) and in one nonconsanguineous American DUH-affected pedigree (family III), three heterozygous mutations encoding amino acid substitutions in SAM and SH3 domain containing I (SASH1) were found in the three pedigrees. The substitution mutations in SASH1 gene were as follows: a TAC → GAC substitution at nucleotide 2126 in exon 14, causing a Y551D (p.Tyr 551 Asp) mutation at codon 551 in family I, a CTC → CCC substitution at nucleotide 2019 in exon 13, causing a L515P (p.Leu to Pro) mutation at codon 515 in family II, and a GAA → AAA substitution at nucleotide 2000 in exon 13, resulting in a E509K (p.Glu to Lys) mutation in family III. These sequence alterations were identified in all of the affected pedigree members, but were not observed in unaffected pedigree members, correlating the presence of the mutations with the presence of the phenotype. In any of the 500 normal controls or in any of the current databases, including the HapMap database, these three SASH1 mutations were not found [18]. So, these three mutations are impossible to be common single nucleotide polymorphisms (SNPs) [8].
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In A375 stable cells with ectopic SASH1 gene mutants, mutated SASH1 were found to be significantly up-regulated (Figure 1B). Western blot showed that up-regulation of SASH1 was found in A375 cells stably expressing either wild-type (WT-A375 cells) or mutant SASH1, when compared to the expression of endogenous SASH1 in A375 cells with expression of pBABE-puro empty vector (VECTOR-A375 cells) or BLANK-A375 cells (Figure 1B) [18].
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Figure 1.
Increased SASH1 expression is induced by mutations in SASH1 in vitro and in vivo. (A) Substitution mutation sites in the SASH1 gene in three DUH pedigrees. (B) Differential and increased expression of mutant SASH1 proteins is detected compared to that of wild-type SASH1 in different A375 cells by immunoblot. (C) Immunohistochemistry detection of SASH1 and Mitf. Heterogeneous SASH1 protein was detected in all of the DUH-affected epithelial layers compared to that of normal controls (NC). Heterogeneous distribution of melanocytes is detected in the epithelial layers of DUH-affected individuals using Mitf compared to that of normal controls. 400× magnification. Scale bar = 20 μm. The representative positive cells of SASH1 and Mitf were denoted by red arrows.
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To identify the stability of SASH1 proteins, 20 μg/ml of the protein synthesis inhibitor cycloheximide (CHX) was used to treat HEK-293T stable cells with ectopic wild-type or mutant SASH1 expressing for the indicated times to assess the half-life of SASH1. SASH1 protein levels were induced to decrease by CHX treatment in a time-course-dependent manner. Wild-type SASH1 levels was decreased with a half-life of approximately 4 h, however, mutant SASH1 proteins began to degrade with CHX treatment for 6 h or longer. Therefore, it is deduced that the three mutant SASH1 proteins were more steady than the wild-type, confirming the conclusion offered above that expression levels of mutated SASH1(s) are higher levels than that of wild-type (Figure 2A and B). Endogenous SASH1 was not a stable protein with an half-life of approximately 3 h as identified by western blot (Figure 2C) [18].
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Figure 2.
Endogenous SASH1 protein is unstable and mutation of SASH1 induces the heterogeneous expression of SASH1 in vitro. (A) Mutant SASH1 proteins are more stable than the wild-type SASH1 protein. Stable HEK-293T cells were treated with CHX (20 μg/ml) for the indicated times and analyzed by western blotting. The amount of SASH was quantified by densitometry and normalized to β-tubulin. CHX resulted in the degradation of wild-type SASH1 protein, which had a half-life of 4 h. Under a 6-h or longer treatment with CHX, CHX began to induce the degradation of mutant SASH1 proteins. (B) The intensity of GFP-SASH1 was quantified by densitometry and normalized to β-tubulin (n = 3). (C) Endogenous SASH1 is an unstable protein. HEK-293T cells were deprived of FBS for the indicated time and lysed and subjected to western blot to detect the endogenous SASH1 levels.
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The subcellular localization of SASH1 in A375 cells and skin epithelial layers was further characterized. A homogenous pattern of expression of SASH1 protein was observed in VECTOR-A375 cells and the skin epithelial layers from normal controls (Figures 1C and 3-a4). However, heterogeneity expression of SASH1 protein was showed in WT-A375 cells and mutant-A375 cells (Figure 3-b4–e4) as well as in the epithelial tissues of affected individuals (Figure 1C). In addition, as identified by Mitf, a melanocyte indicator, most of the SASH1-positive cells were Mitf-nucleic positive-melanocytes in the epithelial tissues of DUH-affected individuals. These Mitf-nucleic positive-melanocytes in the affected epithelial layer showed a heterogeneous distribution compared to those of unaffected individuals (Figure 1C). Some Mitf-tenuigenin-positive staining is of false positivity (Figure 1C). Melanocytes or SASH1-positive epithelial cells not only localized at the basal layers, but also the suprabasal layers of the affected epidermal tissue, the phenomenon of which coincides with our previous descriptions that SASH1 mutations promotes melanocyte movement from the affected basal layers to the superficial ones [13].
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Figure 3.
Subcellular localization of SASH1. The fluorescence signals that were detected by confocal microscopy indicate that the overexpression or mutation of SASH1 results in the heterogeneous expression of SASH1 in vitro in A375 stable cells. The green fluorescence represents the Flag-tag label. Both exogenous and endogenous SASH1 are labeled with a red fluorescent tag. The nuclei are labeled with DAPI (in blue). The yellow fluorescence indicates the overlap of the green and red fluorescent staining. The red arrowheads indicate the activated SASH1-Flag fusion proteins that were expressed in the cytoplasm of WT-A375 cells or mutant-A375 cells. The blue arrowheads indicate the regions that do not express the activated SASH1-Flag fusion protein in the cytoplasm of WT-A375 or mutant-A375 cells. The endogenous SASH1 presents a uniform pattern of expression in all of the VECTOR-A375 cells (Figure 3A-a4). Scale bar = 5 μm.
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3.2 SASH1 binds to Gαs and is induced by the canonical p53/POMC/Gαs cascade
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SASH1 contains two functional domains, SAM and SH3 domain, which indicates SASH1 may plays an important role in a signaling pathway acting as a signaling molecule adapter or an associated scaffolding protein [8, 9]. Therefore, we performed a pull-down assay and a mass spectrometry analysis to investigate which signaling pathways are regulated by SASH1. Pull-down experiments and nanoflow LC-MS/MS analysis demonstrated that SASH1 interacts with Gαs and CALM, both of which are important in melanogenesis process (Tables 3 and 4) in WT-A375 cells. Gαs connects receptor-ligand associations with the activation of adenylyl cyclase and many cellular responses, serving as a pivotal player in the conventional signal cascades [20]. To investigate the associations between SASH1 and Gαs, HEK-293T cells were co-transfected with Flag-SASH1 and GFP-Gαs. Exogenous SASH1 was immunoprecipitated with both exogenous Gαs (GFP-Gαs) and endogenous Gαs. Immunoprecipitates of exogenous SASH1 had different observed band sizes of Gαs (Figure 4B and C) [18].
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Protein name
\n
Score
\n
Protein possibility
\n
Total peptide
\n
Unique peptide
\n
\n\n\n
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SASH1
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200.3
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1
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37
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20
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Gαs
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20.2
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1
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8
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5
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CALM1
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10.2
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1
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7
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3
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Table 3.
Proteins interacting with SASH1 were identified by MS analysis.
Affinity-purified proteins were identified by MS analysis and the detailed peptide sequences are summarized in Table 2.
SBP-FLAG-SASH1 affinity purification was performed to identify the peptide sequences of the binding complex of SASH1 protein.
A375 stable cells with ectopic SBP-FLAG-SASH1 expressing were lysed, immunoprecipitated with SBP beads and digested with trypsin. The liquid supernatant was collected, dried, and dissolved in 10% (v/v) acetonitrile and 0.8% formic acid solution. Nanoflow LC-MS/MS analyses were performed to identify the peptides.
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Figure 4.
Gαs binds to SASH1 and is a central downstream player of p53/POMC cascade. (A) Immunoprecipitation-Western blot (IP-WB) was performed to identify the interactions between GFP-SASH1 and endogenous Gαs in HEK-293T cells. pEGFP-C3-SASH1-recombined vectors were introduced into HEK-293T cells. At 24 h after transfection, GFP-SASH1 was immunoprecipitated and the associated endogenous Gαs was identified by immunoblot analysis using a Gαs antibody. (B) Exogenous Gαs binds to exogenous SASH1. pEGFP-C3-Gαs and pBABE-puro-Flag-SASH1 vectors were co-introduced into HEK-293T cells. At 36 h after transfection, exogenous SASH1 (Flag-SASH1) was immunoprecipitated and the associated GFP-Gas was detected by western blot analysis using an anti-GFP antibody. At 36-h post-transfection, Flag-SASH1 was immunoprecipitated and the associated exogenous Gαs (GFP-Gas) was detected by immuoblot using an anti-GFP antibody. (C) and (D) P53, POMC, and SASH1 are essential to the activation of Gαs. HA-p53, myc-POMC, and GFP-SASH1, respectively, according to different manners of combination were introduced into HEK-293 cells and NHEMs. After 36 h after transfection, immunoblotting was performed to detect the protein levels in two normal cells along with GAPDH as loading control. (E) Exogenous Gαs (GFP-Gαs) is induced by exogenous p53 (HA-p53). HEK-293 cells were transfected with HA-p53 and GFP-Gαs. At 36-h post-transfection, the transfected HEK-293 cells were lysed and subjected to western blot analyses. GFP-Gαs was induced by gradually increased amounts of HA-p53. (F) Exogenous Gαs (GFP-Gαs) is induced by exogenous SASH1 (GFP-Gαs). GFP-Gαs and GFP-SASH1 were transfected into HEK-293T cells. GFP-Gαs was induced by gradually increased doses of GFP-SASH1. (G) and (H) Exogenous POMC (myc-POMC) was induced by increased dose of exogenous p53 in HEK-293T cells and NHEMs. Different amounts of HA-p53 vector and a certain amounts of myc-POMC vector were introduced into HEK-293T cell for expression. Exogenous POMC RNA levels were quantified by quantitative RT-PCR and normalized to GAPDH. The expression of HA-p53 and myc-POMC was analyzed by immunoblot using GAPDH as loading control.
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Gαs mediates cAMP production in melanocytes which is stimulated by α-MSH and melanocortins [21] and our study here shows that Gαs is associated with SASH1. Hence, we examine whether Gαs is required for the induction of SASH1 and how Gαs mediates SASH1 expression, we introduced exogenous p53, POMC, Gαs, and SASH1 gene into HEK-293T and NHEMs (normal human epithelial melanocytes) to assess the effects of p53 and POMC on Gαs. Exogenous Gαs was induced in the co-existence of exogenous p53 and POMC (Figure 4C lane 5 and Figure 4D lane 5) and both inducements of exogenous Gαs and exogenous SASH1 were observed in the co-existence of exogenous p53 and POMC in two types of normal cells (Figure 4C lane 6 and Figure 4D lane 6). Meanwhile, in the presence of GFP-SASH1, GFP-Gαs was also induced (Figure 4C lane 4 and Figure 4Dlane 4), which indicated that SASH1 is necessary for activation of GFP-Gαs. And immunoblot showed that Gαs was identified to be induced by exogenous p53 and SASH1 (Figure 4E and F). Our results also demonstrated that POMC was mediated by p53 in HEK-293T and melanocytes, which were consistent with previous conclusions [1] (Figure 4G and H).
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To confirm the fact that POMC, p53, and Gαs are needed for the induction of SASH1 and exogenous POMC, p53, Gαs, and SASH1 were transfected into HEK-293T cells and followed by silence of Gαs and POMC by two specific pairs of siRNA, respectively. As identified in HEK-293 cells, deletion of Gαs gene directly induced significant reduction of SASH1 (Figure 5C and D). Deletion of POMC by siRNA resulted in the downregulation of Gαs and SASH1 (Figure 5E and F). Taken above, it is believed that Gαs serves as a pivotal downstream of p53/POMC cascade and SASH1 is regulated by a novel p53/POMC/Gαs cascade.
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Figure 5.
Expression of SASH1 was mediated by a novel p53/POMC/Gαs/SASH1 signal cascade. (A) and (B) Endogenous and exogenous SASH1 (GFP-Gαs) are both induced by Gαs. HEK-293T cells were transfected with gradually increasing doses of exogenous Gαs and exogenous SASH1, or only different amounts of exogenous Gαs. The protein levels of endogenous or exogenous SASH1 were assessed by immunoblot. (C) and (D) Gαs is essential for the induction of SASH1. Exogenous Gαs, POMC, and SASH1 as well as increasing doses of HA-p53 according to different combinations were transfected into HEK-293 cells. Among the transfected HEK-293 cells, two groups of cells were afterward transfected with two pairs of effective Gαs siRNAs and negative control (NC) siRNA. The corresponding protein levels were assessed by western blot. (E) and (F) POMC is essential for the induction of SASH1 and Gαs. HEK-293 cells were transfected with GFP-Gαs, myc-POMC, and GFP-SASH1 as well as increasing dose of HA-p53 according to different manner of combinations. Among the transfected HEK-293 cells, two groups of HEK-293 cells were later silenced with two pairs of effective POMC siRNAs and NC siRNA.
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3.3 P53 physiologically triggers SASH1 upon UV irradiation
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To reveal the phenomenon that P53 physiologically triggers SASH1, discarded normal human foreskin samples were irradiated to gradually increased dose of UV and stained for the histological analyses of p53, ACTH/POMC, and SASH1. Immunohistochemical (IHC) analyses demonstrated p53 is quickly induced in basal layers at the 0.5 J/cm2 dose of UV exposure. The quick inducement of SASH1 and POMC/ACTH at UV irradiation 1.0 J/cm2 dose in melanocytes is followed closely by p53 up-regulation (Figure 6A). Previous study had indicated that up-regulated POMC gene is induced at both protein and mRNA levels following UV exposure of skin [22, 23]. Followed the previous reports [1], a 100 J/m2 UVB dose was administered in this study. The 100 J/m2 UVB dose equates to the standard erythema dose (SED), which is commonly used as a measure of sunlight [24]. Therefore, both endogenous p53 and SASH1 protein levels in HEK-293T cells and NHEMs with ectopic exogenous POMC after UV irradiation were assessed by immunoblot. Expression of exogenous POMC and endogenous SASH1 was markedly induced by 6 h after UV irradiation, which accords with its known stabilization by UV in NHEMs. At 24 h, in NHEMs, UV irradiation maximally promoted the expression of POMC, p53, and SASH1 protein (Figure 6B). Similar induction of exogenous POMC and endogenous p53 and SASH1 was detected in HEK-293T cells after UV irradiation (Figure 6C). Hence, it is believed that both POMC and SASH1 serve as novel downstream players which respond to p53 inducement by UV irradiation.
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Figure 6.
SASH1 is induced physiologically by p53 after UV irradiation. (A) Upon UV irradiation or without UV irradiation, immunohistochemistry analyses of p53, POMC, and SASH1 in human foreskin indicated that p53 is activated by UV-induced-increase of POMC and SASH1. The human foreskin tissues obtained from a 14-year-old boy were irradiated at different doses of UV intensity, then fixed in 10% formalin and embedded in paraffin for immunohistochemical analyses. Scale bar: 20 μm. The representative positive cells of p53, ACTH, and SASH1 were donated by red arrows. (B) and (C) NHEMs and HEK-293T cells with ectopic exogenous POMC (myc-POMC) expression were irradiated with UV irradiation (100 mJ/cm2) and recovered for the indicated times. Transfected cells were lysed and at different time-points after irradiation as indicated. Western blot was used to detect the protein levels of endogenous p53, endogenous SASH1, and exogenous POMC along with GAPDH or beta-tubulin as a loading control.
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3.4 p53-SASH1 reciprocal inducement in normal cells
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To assess whether p53 is required for the inducement of SASH1, exogenous p53, and POMC gene were transfected into HEK-293T and NHEMs to test the induction of p53 and POMC to SASH1. In NHEMs and HEK-293T cells with ectopic of POMC (myc-POMC) in NHEMs and HEK-293T cells, exogenous SASH1 were induced to up-regulate by p53 (Figure 7). Increased protein levels of exogenous SASH1 was induced by increasing amounts of exogenous p53 in two normal cells (Figure 8A and B). On the contrary, exogenous p53 (HA-p53) was also triggered by increasing amounts of exogenous SASH1 (Figure 8C and D). The induction of exogenous SASH1 to endogenous p53 was also identified. It has been documented that, in two types of normal cells, increased endogenous p53 was induced by increasing doses of exogenous SASH1 (Figure 8E and F).
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Figure 7.
Exogenous p53 triggers expression of SASH1. (A) Exogenous p53 caused up-regulation of exogenous SASH1 in HEK-293T cells. HA-TP53, GFP-SASH1, and myc-POMC were transfected into HEK-293T cells for transient expression. Cells were lysed in 0.5% NP40 buffer containing protease inhibitors and subjected to western blot along with GAPDH as loading control. (B) Exogenous p53 caused up-regulation of exogenous SASH1 in NHEMs.
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Figure 8.
There is a reciprocal induction between p53 and SASH1 in normal cells. (A) and (B) Exogenous SASH1 was triggered by exogenous p53 (HA-p53) in a dose-dependent manner. Different amounts of HA-TP53 plasmid were introduced into HEK-293T cells and NHEMs as indicated. After 48-h post-transfection or transfection, total RNA of HEK-293T cells and NHEMs was extracted and exogenous SASH1 RNA levels were assessed by quantitative RT-PCR and normalized to GAPDH. Expression of exogenous p53 protein and SASH1 were analyzed by western blot along with GAPDH as a loading control. (C) and (D) Protein and RNA levels of exogenous p53 were promoted by exogenous SASH1 promotes expression. Different amounts of GFP-SASH1 plasmid and a certain amount of exogenous p53 were transfected to HEK-293T cells and NHEMs cells. As revealed by QRT-PCR and western blot, enhanced expression of exogenous TP53 was induced by increasing amounts of GFP-SASH1. (E) and (F) Increased endogenous p53 was induced by exogenous SASH1. Different amounts of GFP-SASH1 were transfected in to HEK-293T cells and NHEMs. At 36 h after transfection, cells were lysed and subjected to western blot to analyze the expression of GFP-SASH1 with GAPDH as loading control. Results are the representative of three independent experiments. (G) A novel reciprocal induction of p53 and SASH1 is mediated by an autoregulatory p53/POMC/Gαs/SASH1 loop. p53 is activated by different types of stress, which fosters POMC, Gαs, and SASH1 successively. The inducement of SASH1 by p53/POMC/Gαs cascade promotes the up-regulation p53 in nucleus, then induced nucleic p53 conversely activates POMC/Gαs/SASH1 cascade, which consists an autoregulatory p53/POMC/Gαs/SASH1 loop.
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Since SASH1 is mediated by p53, we want to investigate whether there is a direct relationship between SASH1 and p53. As indicated in Figure 9A and B, HA-p53 did not bind to GFP-SASH. So, we tested the proximal 1 kb promoter region of the SASH1 gene to find the consensus transcription-factor-binding elements that are conserved between human, rat, and mouse. Among the various consensus elements searched for, p53 gene was remarkable. A most possible p53-binding site, sequence of which is “tgcccaagctttcacacttgttt” was identified in the SASH1 5′ flanking region about 550 bp upstream of the transcription initiation site in humans (Figure 9C). So, three synthesized probes were used to investigate the associations of p53 protein with SASH1 gene promoter. However, analyses of electrophoretic mobility shift assay (EMSA) revealed that there was no p53 protein bind the promoter region of the SASH1 gene (Figure 9D).
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Figure 9.
p53 is not associated with SASH1 and SASH1 is not transcriptionally regulated by p53. (A) and (B) HEK-293T cells were co-transfected with the pEGFP-C3-SASH1 and Pcdna 3.0-HA-p53 vectors. At 24-h post-transfection, GFP-SASH1 was immunoprecipitated and the associated HA-p53 was detected by western blot analysis using an anti-HA antibody. Similarly, HA-p53 was immunoprecipitated and the associated GFP-SASH was detected by western blot analysis using an anti-GFP antibody. (C) Showed a schematic representation of the SASH1 locus, which indicates location of a p53-binding consensus sequence. (D) EMSA analyses demonstrated that there was none of among three probes of SASH1 gene promoter to bind p53 recombined protein.
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In summary, it is believed that SASH is regulated by the p53/POMC/α-MSH/Gαs signal cascade and p53/POMC/α-MSH/Gαs cascade and SASH1 constitute a novel autoregulatory loop. The p53/POMC/α-MSH/Gαs/SASH1 regulatory loop acts as an auto-feedback circuit to regulate the p53-SASH1 reciprocal inducement (Figure 8G).
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3.5 Enhance expression of p53 and POMC is induced by SASH1 mutations
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SASH1 up-regulation is mediated by SASH1 mutations, which is unfathomable enigma to us for lone time. Therefore, HEK-293T cells and NHEMs were transfected with wild-type or mutant SASH1 (wt SASH1 or mut SASH1), exogenous p53 and exogenous POMC to assess the effects of SASH1 mutations on p53 and POMC. As demonstrated in Figure 10A and B, increased expression of p53 and POMC was induced by SASH1 mutations. The effects of SASH1 mutations on endogenous p53 at protein level were also assessed. Increased endogenous p53 was also induced by mutated SASH1 (Figure 10C and D). In order to identify that p53 is induced by SASH1 mutations in vivo, immunostaining of p53 in the affected epithelial tissues with SASH1 Y551D mutation was performed. IHC analyses indicated that more nucleic expression of p53 in epithelial tissues and more p53-positive cells in affected epithelia layers were induced by SASH1 Y551D mutation (Figure 10E).
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Figure 10.
p53 and POMC are induced to be increased SASH1 mutations. (A) and (B) Up-regulated SASH1 induced by SASH1 mutations promotes the expression of exogenous p53 and exogenous POMC in HEK-293T cells and NHEMs. Wt and mutant SASH1, exogenous p53 and exogenous POMC were introduced into HEK-293T cells and NHEMs. At 48-h post-transfection, immunoblot were performed to detect the corresponding protein levels. (C) As identified by IHC analyses, high expression of endogenous p53 was induced by Y551D-SASH1 mutation and more p53-positive epithelial cells were detected in the affected epithelial tissues. Affected epithelial tissues with Y551D SASH1 mutation from pedigree I as well as normal epithelial tissues were fixed and embedded in paraffin for immunohistochemistry detection. Scale bar: 20 μm. The representative positive cells of p53 are donated by red arrows. (D) and (E) Western blot indicated that increased endogenous p53 was induced by SASH1 mutations in HEK-293 cells and NHEMs.
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All of these indicate that not only SASH1 is positively regulated by the p53/POMC/α-MSH/Gαs/SASH1 autoregulatory loop, but also SASH1 mutations serve more as molecular rheostats rather than an on-off switch to control this regulatory loop.
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3.6 Expression of melanosomes matrix molecules was triggered by SASH1 mutations
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Since there is a SASH1-p53 autoregulatory loop, the changes of downstream partners of SASH1 need to be tested. Therefore, we further identified the effects of mutated SASH1 on the protein levels of matrix proteins and transport proteins. Enhanced expression of TYRP1, Rab 27a, Pmel17, and tyrosinase in SK-MEL-28 cells, a pigmented melanoma cell line and NHEMs was significantly induced by SASH1 mutations (Figure 11A and B). QRT-PCR also indicated that Pmel17, TYRP1, and Rab 27a were up-regulated by mutations of SASH1 in SK-MEL-28 stable cells (Figure 11C). Pmel17, TYRP1, and Rab 27a was heterogeneously distributed in the epithelial cells in the tissues of DUH-affected individuals as demonstrated by IHC analyses (Figure 11D and E). Increased levels of melanogenesis molecules were observed in some hyperpigmentation areas in the affected epithelial layers. In the hyperpigmentation plaques, the superfluous production and secretion of melanin was clearly presented in the basal layers and in the suprabasal layers of the affected epidermal as (Figure 11D).
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Figure 11.
Increased production of melanogenic components and heterogeneous distribution of melanin in vivo were induced by SASH1 mutations. (A) Up-regulation of melanogenic components including TYRP1, Pmel17, tyrosinase, and Rab 27a were induced by SASH1 mutations in stable SK-MEL-28 cells. (B) Up-regulation of Rab 27a and tyrosinase was also induced by SASH1 mutations. The SASH1 gene (wt and mutant) was introduced into NHEMs and western blot was performed to determine the effect of SASH1 mutations on melanogenic components. (C) As identified by QRT-PCR, up-regulation of Pmel17, TYRP1, and Rab 27a in stable SK-MEL-28 cells was induced by SASH1 mutations (n = 4, mean ± standard error). (D) As identified by immunochemistry detection, heterogeneous distribution of Rab 27a and melanin were observed in the epithelial layers of the affected individuals. (E) Immunochemical analyses indicated that expression of Pmel17 and TYRP1 was heterogeneously distributed in all of the epithelial layers of the epidermal tissues from the DUH-affected individuals. Pmel17, TYRP1, and Rab 27a: 400× magnification, bar = 20 μm; melanin: 1000 magnification. Scale bar: 20 μm. The representative positive cells of Rab 27a, Pmel17, TYRP1, and melanin were indicated by red arrows.
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4. Conclusion
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Our study reveals that a novel p53-SASH1 reciprocal induction triggers pigmentation of skin through an autoregulatory p53/POMC/α-MSH/Gαs/SASH1 loop. SASH1 mutations enhance SASH1-mediated induction of p53 and POMC. POMC is induced by p53 overexpression and resulted in UV-dependent hyperpigmentation UV-independent pathological hyperpigmentation [1]. Our work indicates that POMC up-regulation is induced by SASH1 mutations, which ultimately results in the pathological hyperpigmentations of affected DUH individuals. These data indicate that SASH1 activation induced by mutations in melanocytes acts as a “UV sensor/effector” for skin pigmentation or SASH1 mutations-mediated up-regulation is the “chief criminal” of pathological hyperpigmentation of DUH, and its underlying mechanistic role is SASH1-p53 reciprocal inducement. Our data indicate that the definitions of the positive feedback p53/POMC/α-MSH/Gαs/SASH1 loop help us to recognize an important linkage between the p53 pathway and MC1R pathway by SASH1.
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Recently, a c.1067T>C (p.Leu356Pro) mutation in exon 3 of ABCB6 (ATP-binding cassette subfamily B, member 6) was found in a large five-generation Chinese family with DUH family. Two additional missense mutations, c.508A>G (p.Ser170Gly) in exon 1 and c.1736G>A (p.Gly579Glu) in exon 12 of ABCB6 were found in two out of six patients using sporadic DUH patients [25]. Ac.1663C>A, (p.Gln555Lys) missense mutation in ABCB6 was identified in a Chinese family with typical features of autosomal dominant DUH. Two deletion mutations (g.776 delC, c.459 delC) in ABCB6 were found in an unrelated sporadic affected individual [26]. In addition, missense mutations in ABCB6 were also found in the sporadic affected DUH individuals [27, 28]. Silence of ABCB6 by siRNA destroyed PMEL amyloidogenesis in early melanosomes and resulted in aberrant increase of multilamellar aggregates in pigmented melanosomes. In the retinal pigment epithelium of ABCB6 knockout mice, morphological analysis indicated an obvious decrease of melanosome numbers [29]. All of these sequencing results and functional analyses of causing genes responsible for DUH indicate there exist novel pathogenicity genes and novel gene variations which is responsible for pathogenesis of DUH or there exists novel subtype of DUH.
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The transcriptional network of p53-responsive genes produces proteins that interact with a large number of other signal transduction pathways in the cell and a number of positive and negative autoregulatory feedback loops act upon the p53 response [30]. Feedback loops of p53 and p53-responsive genes provide a means to connect the p53 pathway with other signal transduction pathways and coordinate the cellular signals for growth and division [30]. Our findings suggest that SASH1 serves as a “Hinge” to connect p53/POMC/α-MSH pathway with MC1R/Gαs/cAMP/PKA cascade to form an autoregulatory p53/POMC/Gαs/SASH1 circuit to mediate the melanogenesis process [18, 31].
\n
Most recently, SASH1 is showed to involve in autosomal-dominant lentiginous [32] and autosomal-recessive SASH1 variants (c.1849G>A; p.Glu617Lys), which are associated with a new genodermatosis with a pigmentation defects, palmoplantar keratoderma and skin carcinoma and SASH1 is first reported to be predisposed to skin cancer [33]. Dyschromatosis universalis hereditaria (DUH) is a clinically heterogeneous disorder that presents as generalized mottled pigmentation and was first reported by Ichigawa and Hiraga in 1933 [7]. Stuhrmann and colleagues identified the first locus responsible for autosomal-recessive DUH, and this findings is consistent with recent evidence demonstrating that DSH and DUH are genetically distinct disorders [34]. Zhang et al. mapped the causative gene of DSH to 1q11-1q21 and found that a novel mutation of a heterozygous nucleotide A → G at position 2879 in exon 10 of the DSRAD gene is involved in DSH [35]. Subsequent research on dyspigmentation has demonstrated that the pathogenic genetic variant that causes DSH is localized to the DSRAD gene on chromosome 1q [15, 36, 37, 38, 39, 40, 41]. Expanding Stuhrmann and Nuber’s findings and our own previous work providing photographic evidence of dyschromatosis presenting as large hyperpigmented bodies on DUH-affected individuals [6, 8, 34], we believe that we have discovered the first locus associated with autosomal dominant DUH, identifying SASH1 as the causative gene of autosomal dominant DUH.
\n
Our findings first identify the pathological gene of DUH and reveal the pathological mechanism of hyperpigmentation patches of DUH-affected individuals. In addition, our work will enrich the crosstalk of p53 pathway with other transduction pathways in cells and give a new definition of the p53-responsive genes and their associations, which will perfect the p53 programmed responses to stress and pathologic conditions.
\n
\n
Acknowledgments
\n
We thank Central Laboratory at Yongchuan Hospital, Chongqing Medical University and Clinical Research Center, the Affiliated Hospital, Guizhou Medical University for housing the experiments. This work was supported by the Shanghai Municipal Commission of Science and Technology Program (09DJ1400601), the 973 Program (2010CB529600, 2007CB947300), the Yongchuan Hospital Project, Chongqing Medical University (YJYJ201347), Chongqing Education Commission Project (KJ1400201), and Guizhou’s Introduction Project of Million Talents.
\n
Conflict of interest
No conflict between the authors.
\n
Notes/thanks/other declarations
\n
The chapter text was mainly referred to our article entitled as “A Novel P53/POMC/Gαs/SASH1 Auto-regulatory Feedback Loop Activates Mutated SASH1 to Cause Pathologic Hyper-pigmentation” (Journal of Cellular and Molecular Medicine 2017, 21(4):802-815) which we published in journal of cellular and molecular medicine in April, 2017. In this chapter, we rewrite the chapter text according to the suggestions of reviewers.
\n
The chapter figures were taken from the figures and supplementary figures of our article entitled as “A Novel P53/POMC/Gαs/SASH1 Auto-regulatory Feedback Loop Activates Mutated SASH1 to Cause Pathologic Hyper-pigmentation”. The chapter tables were taken from the supplementary tables of our published article.
\n
\n
Declarations
\n
Our article entitled as “A Novel P53/POMC/Gαs/SASH1 Auto-regulatory Feedback Loop Activates Mutated SASH1 to Cause Pathologic Hyper-pigmentation” is an Open Access article published under the terms of the Creative Commons Attribution License (CC BY). We are allowed to reuse the material without having to obtain permission provided that the original source of publication.
\n
Appendices and nomenclature
ABCB6
ATP-binding cassette subfamily B, member 6
ACTH
adrenocorticotropic
α-MSH
α-melanocyte stimulating hormone
cAMP
cyclic adenosine monophosphate
CDS
coding sequence
CHX
cycloheximide
DSRAD
double-stranded RNA-specific adenosine deaminase
DSH
dyschromatosis symmetrica hereditaria
DUH
dyschromatosis universalis hereditaria
EMSA
electrophoretic mobility shift assay
GAPDH
glyceraldehyde phosphate dehydrogenase
Gαs
guanine nucleotide-binding protein subunit-alpha isoforms short
\n',keywords:"SASH1 substitution mutations, p53, autoregulatory feedback loop, DUH, pathological hyperpigmentation phenotype",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/64249.pdf",chapterXML:"https://mts.intechopen.com/source/xml/64249.xml",downloadPdfUrl:"/chapter/pdf-download/64249",previewPdfUrl:"/chapter/pdf-preview/64249",totalDownloads:159,totalViews:0,totalCrossrefCites:0,dateSubmitted:"July 29th 2018",dateReviewed:"September 18th 2018",datePrePublished:"November 5th 2018",datePublished:"November 6th 2019",readingETA:"0",abstract:"P53-regulated proteins in transcriptional level are associated with many signal transduction pathways and p53 plays a pivotal role in a number of positive and negative autoregulatory feedback loops. Although POMC/α-MSH productions induced by ultraviolet (UV) are directly mediated by p53, p53 is related to UV-independent pathological pigmentation. In the process of identifying the causative gene of dyschromatosis universalis hereditaria (DUH), three mutations encoding amino acid substitutions were found in the gene SAM and SH3 domain containing 1 (SASH1). SASH1 was identified to interact with guanine nucleotide-binding protein subunit-alpha isoforms short (Gαs). However, for about 90 years, the pathological gene and the pathological mechanism of DUH are unclear. Our study indicates that SASH1 is physiologically medicated by p53 upon UV stimulation and a reciprocal SASH-p53 inducement is existed physiologically and pathophysiologically. A novel p53/POMC/α-MSH/Gαs/SASH1 signal cascade regulates SASH1 to foster melanogenesis. SASH1 mutations control a novel p53/POMC/Gαs/SASH1 autoregulatory positive feedback loop to promote pathological hyperpigmentation phenotype in DUH-affected individuals. Our work illustrates a novel p53/POMC/Gαs/SASH1 autoregulatory positive feedback loop that is mediated by SASH1 mutations to foster pathological hyperpigmentation phenotype.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/64249",risUrl:"/chapter/ris/64249",signatures:"Ding’an Zhou, Jiawei Zeng, Xing Zeng, Yadong Li, Zhixiong Wu, Xin Wan, Pingshen Hu and Xiaodong Su",book:{id:"8400",title:"Molecular Medicine",subtitle:null,fullTitle:"Molecular Medicine",slug:"molecular-medicine",publishedDate:"November 6th 2019",bookSignature:"Sinem Nalbantoglu and Hakima Amri",coverURL:"https://cdn.intechopen.com/books/images_new/8400.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"147712",title:"Dr.",name:"Sinem",middleName:null,surname:"Nalbantoglu",slug:"sinem-nalbantoglu",fullName:"Sinem Nalbantoglu"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"269666",title:"Dr.",name:"Dingan",middleName:null,surname:"Zhou",fullName:"Dingan Zhou",slug:"dingan-zhou",email:"460318918@qq.com",position:null,institution:null},{id:"271158",title:"Dr.",name:"Jiawei",middleName:null,surname:"Zeng",fullName:"Jiawei Zeng",slug:"jiawei-zeng",email:"1075650644@qq.com",position:null,institution:null},{id:"271159",title:"Prof.",name:"Pingsheng",middleName:null,surname:"Hu",fullName:"Pingsheng Hu",slug:"pingsheng-hu",email:"hups@sinorda.com",position:null,institution:null},{id:"271160",title:"Prof.",name:"Xiaodong",middleName:null,surname:"Su",fullName:"Xiaodong Su",slug:"xiaodong-su",email:"xdsu@pku.edu.cn",position:null,institution:null},{id:"272519",title:"Mr.",name:"Xing",middleName:null,surname:"Zeng",fullName:"Xing Zeng",slug:"xing-zeng",email:"1025271442@qq.com",position:null,institution:null},{id:"272520",title:"Mr.",name:"Yadong",middleName:null,surname:"Li",fullName:"Yadong Li",slug:"yadong-li",email:"2044016325@qq.com",position:null,institution:null},{id:"272521",title:"Mr.",name:"Zhixiong",middleName:null,surname:"Wu",fullName:"Zhixiong Wu",slug:"zhixiong-wu",email:"1594340761@qq.com",position:null,institution:null},{id:"272523",title:"Mr.",name:"Xing",middleName:null,surname:"Wan",fullName:"Xing Wan",slug:"xing-wan",email:"610220274@qq.com",position:null,institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Materials and methods",level:"1"},{id:"sec_2_2",title:"2.1 DUH pathologic gene sequencing and SASH1 mutation analysis",level:"2"},{id:"sec_3_2",title:"2.2 Constructing expression vectors of SASH1, Gαs, POMC, and p53",level:"2"},{id:"sec_4_2",title:"2.3 Culture of cell and vector transfection",level:"2"},{id:"sec_5_2",title:"2.4 Pull-down experiments and nanoflow LC-MS/MS and bioinformatic assays",level:"2"},{id:"sec_6_2",title:"2.5 Immunoprecipitation and westernblotting",level:"2"},{id:"sec_7_2",title:"2.6 Immunohistochemical analyses and immunofluorescence staining and melanin staining",level:"2"},{id:"sec_7_3",title:"2.6.1 Immunohistochemistry",level:"3"},{id:"sec_8_3",title:"2.6.2 Immunofluorescence (IF) and confocal microscopy detection",level:"3"},{id:"sec_9_3",title:"2.6.3 Melanin staining",level:"3"},{id:"sec_11_2",title:"2.7 Quantitative RT-PCR",level:"2"},{id:"sec_12_2",title:"2.8 UV irradiation",level:"2"},{id:"sec_13_2",title:"2.9 Electrophoretic mobility shift assay",level:"2"},{id:"sec_14_2",title:"2.10 Statistical analyses",level:"2"},{id:"sec_16",title:"3. Results",level:"1"},{id:"sec_16_2",title:"3.1 Mutations in SASH1 gene in the DUH-affected individuals result in up-regulated SASH1 in vitro and in vivo",level:"2"},{id:"sec_17_2",title:"3.2 SASH1 binds to Gαs and is induced by the canonical p53/POMC/Gαs cascade",level:"2"},{id:"sec_18_2",title:"3.3 P53 physiologically triggers SASH1 upon UV irradiation",level:"2"},{id:"sec_19_2",title:"3.4 p53-SASH1 reciprocal inducement in normal cells",level:"2"},{id:"sec_20_2",title:"3.5 Enhance expression of p53 and POMC is induced by SASH1 mutations",level:"2"},{id:"sec_21_2",title:"3.6 Expression of melanosomes matrix molecules was triggered by SASH1 mutations",level:"2"},{id:"sec_23",title:"4. Conclusion",level:"1"},{id:"sec_24",title:"Acknowledgments",level:"1"},{id:"sec_27",title:"Conflict of interest",level:"1"},{id:"sec_24",title:"Notes/thanks/other declarations",level:"1"},{id:"sec_25",title:"Declarations",level:"1"},{id:"sec_28",title:"Appendices and nomenclature",level:"1"}],chapterReferences:[{id:"B1",body:'Cui R et al. Central role of p53 in the suntan response and pathologic hyperpigmentation. Cell. 2007;128(5):853-864\n'},{id:"B2",body:'Roberts DW et al. Quantitative analysis of MC1R gene expression in human skin cell cultures. Pigment Cell Research. 2006;19(1):76-89\n'},{id:"B3",body:'Rees JL. The genetics of sun sensitivity in humans. American Journal of Human Genetics. 2004;5(75):739-751\n'},{id:"B4",body:'Jiang Y et al. Regulation of G-protein signaling by RKTG via sequestration of the G betagamma subunit to the Golgi apparatus. Molecular and Cellular Biology. 2010;30(1):78-90\n'},{id:"B5",body:'Ananthaswamy HN et al. 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Topical drug rescue strategy and skin protection based on the role of Mc1r in UV-induced tanning. Nature. 2006;443:340-344\n'},{id:"B24",body:'Diffey BL, Jansen CT, Urbach F, Wulf HC. The standard erythema dose: A new photobiological concept. Photodermatology, Photoimmunology & Photomedicine. 1997;13(1-2):64-66\n'},{id:"B25",body:'Zhang C et al. Mutations in ABCB6 cause dyschromatosis universalis hereditaria. The Journal of Investigative Dermatology. 2013;133(9):2221-2228\n'},{id:"B26",body:'Cui YX et al. Novel mutations of ABCB6 associated with autosomal dominant dyschromatosis universalis hereditaria. PLoS One. 2013;8(11):e79808\n'},{id:"B27",body:'Liu H, Li Y, Kwok HK, et al. Genome-wide linkage, exome sequencing and functional analyses identify ABCB6 as the pathogenic gene of dyschromatosis universalis hereditaria. PLoS One. 2014;9(2):e87250\n'},{id:"B28",body:'Lu C, Liu J, Liu F, Liu Y, Ma D, Zhang X. 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Autosomal-recessive SASH1 variants associated with a new genodermatosis with pigmentation defects, palmoplantar keratoderma and skin carcinoma. European Journal of Human Genetics. 2015;23(7):957-962\n'},{id:"B34",body:'Stuhrmann M et al. Dyschromatosis universalis hereditaria: Evidence for autosomal recessive inheritance and identification of a new locus on chromosome 12q21-q23. Clinical Genetics. 2008;73(6):566-572\n'},{id:"B35",body:'Zhang XJ, Gao M, Li M, Li M, Li CR, et al. Identification of a locus for dyschromatosis symmetrica hereditaria at chromosome 1q11-1q21. The Journal of Investigative Dermatology. 2003;120:776-780\n'},{id:"B36",body:'Li W, Li H, Bocking AD, Challis JR. Tumor necrosis factor stimulates matrix metalloproteinase 9 secretion from cultured human chorionic trophoblast cells through TNF receptor 1 signaling to IKBKB-NFKB and MAPK1/3 pathway. Biology of Reproduction. 2010;83(3):484-487\n'},{id:"B37",body:'Li M et al. Mutational spectrum of the ADAR1 gene in dyschromatosis symmetrica hereditaria. Archives of Dermatological Research. 2010;302(6):469-476\n'},{id:"B38",body:'Liu Y et al. Two novel frameshift mutations of the DSRAD gene in Chinese pedigrees with dyschromatosis symmetrica hereditaria. International Journal of Dermatology. 2012;51(8):920-922\n'},{id:"B39",body:'Ren JW et al. Novel frameshift mutation of the DSRAD gene in a Chinese family with dyschromatosis symmetrica hereditaria. Journal of the European Academy of Dermatology and Venereology. 2008;22(11):1375-1376\n'},{id:"B40",body:'Wang XP et al. Four novel and two recurrent mutations of the ADAR1 gene in Chinese patients with dyschromatosis symmetrica hereditaria. Journal of Dermatological Science. 2010;58(3):217-218\n'},{id:"B41",body:'Xing Q et al. Identification of a novel ADAR mutation in a Chinese family with dyschromatosis symmetrica hereditaria (DSH). Archives of Dermatological Research. 2005;297(3):139-142\n'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Ding’an Zhou",address:"460318918@qq.com",affiliation:'
Clinical Research Center, The Affiliated Hospital, Guizhou Medical University, China
Clinical Research Center, The Affiliated Hospital, Guizhou Medical University, China
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