A list of HIF-1α targets with key functions in a variety of physiological cellular processes, such as angiogenesis, survival, and energy metabolism.
Abstract
The hypoxia-inducible factor-1α (HIF-1α) is an evolutionarily conserved transcription factor with prominent roles in the hypoxic response, cell survival, angiogenesis and cancer. HIF-1α functions as a sensor of molecular oxygen: in the presence of oxygen, it is degraded by the proteasome, whereas in reduced oxygen tensions, it heterodimerizes with the constitutively expressed HIF-1b subunit forming the functional HIF1 transcription factor, which enters the nucleus to control expression of hypoxia-inducible genes. Since HIF-1α has been found upregulated in several cancers, it has attracted a lot of clinical interest, because it represents an interesting candidate for pharmacological chemotherapy interventions. In this chapter, we discuss our current knowledge on the HIF1 transcription factors and their major roles in development, physiology, angiogenesis and cancer using examples of recent studies in the model organism Drosophila melanogaster. Given the striking functional conservation between the mammalian and fruit fly HIF-1α, we expect that future studies in the Drosophila model will not only expand our knowledge on the basic HIF1 biology, but they will also pinpoint conserved molecular regulators of HIF1 that might lead to the discovery of novel cancer therapeutics.
Keywords
- hypoxia
- tumorigenesis
- Warburg effect
- metabolism
- tracheogenesis
- inflammation
- Drosophila
1. HIF-1α in mammalian angiogenesis, inflammation and cancer
1.1. Oxygen is required for survival of all animals
Oxygen (O2) is the main ingredient of the atmospheric air and is required for the survival of all living organisms. It is also present in the seas and oceans, and it is necessary for survival of all aquatic living organisms. Oxygen accumulated on Earth’s atmosphere about 2.5 billion years ago [1]. However, it was discovered only 245 years ago, by the chemist Carl Wilhelm Scheele [2]. Its main role in the survival of animals derives from its utilization during cellular respiration. Specifically, oxygen is involved in oxidative phosphorylation, the process that transfers the chemical energy stored in carbon bonds to the phosphate bonds of Adenosine Tri-Phosphate (ATP), which is the main energy carrier in all cell types of living organisms [3]. In addition, oxygen is the main component of ATP production, because it is the final electron acceptor of the respiratory chain. Oxygen-electron reaction leads to the release of reactive oxygen species (ROS), which, when accumulated, results in oxidative stress and eventually cell death [4, 5]. Oxygen is necessary as an energy substrate, and the danger of oxidative damage needs to be kept at equilibrium. Therefore, oxygen homeostasis is critical for all cellular processes, and its intermittent supply results in many pathophysiological conditions, such as myocardial ischemia, sepsis, pulmonary hypertension, chronic obstructive pulmonary disease and cancer, which correspond to frequent causes of mortality in the Western world [6].
The ambient oxygen concentration is 21%, and the cells of the majority of healthy tissues are exposed to less oxygen, which varies between 2 and 16% [6, 7]. Normoxia is defined as normal oxygen levels, whereas hypoxia is a situation where the organism is underprivileged of sufficient oxygen supply. Hypoxia can be continuous or intermittent [4]. In anoxia, oxygen levels are strictly or totally insufficient, and in hyperoxia, oxygen is superfluous in the tissues and organs of the body. Low oxygen levels are mostly observed in acute inflammatory conditions and also within solid tumors [7]. In contrast, hyperoxia might be the result of immoderate oxygen delivery to the organism due to unlimited angiogenesis [8].
Transport of oxygen throughout the bodies of animals is achieved via different mechanisms that depend on the living environment and the size of each organism. For example, in small animals, such as the nematode
1.2. The transcription factor HIF1 is key in oxygen sensing
The hypoxia-inducible factor-1α, HIF-1α, was characterized in 1990 as a transcription factor with a key role in oxygen sensing [10]. The discovery of HIF-1α opened new research avenues focusing on oxygen sensing and oxygen poverty [10]. Despite the discovery of two additional HIFs (the HIF-2α & the HIF-3α) and the variable response of all HIFs to hypoxia, HIF-1α remains the molecule with the major role in oxygen sensing [11, 12].
The importance of HIF-1α and oxygen sensing for living organisms is underscored by the evolutionary conservation of this transcription factor in animals. The genomes of different species ranging from corals to insects to mammals (i.e.,
The human HIF-1α protein is composed of eight regulatory domains: the bHLH DNA binding and dimerization domain, the PAS dimerization domain, the amino-terminal and carboxy-terminal nuclear localization signals (NLS-N and NLS-C), the proline-serine-threonine-rich protein stabilization domain (PSTD), the amino-terminal and the carboxy-terminal transactivation domains (TAD-N and TAD-C), and the transcriptional inhibitory domain (ID). The HIF-1α peptide consists of 826 amino acids, whereas the HIF-1β peptide is smaller with 774 amino acids, because of alternative splicing in a region that encodes 15 residues [9]. Thus, the two HIF1 subunits have highly conserved amino acid sequences for the majority of the regulatory domains described above [22, 23].Apart from HIF1 (HIF-1α and HIF-1β), there are also another two HIFs, the HIF-2α and the HIF-3α, also known as ARNT2 and ARNT3. Their expression is more restricted in human and mouse tissues compared with the HIF-1α and the HIF-1β subunits [24, 25, 26].
The expression of functional HIF-1α is controlled at multiple levels, such as transcription, nuclear transport, protein stability, and transactivation. Most of the studies have focused on the stabilization of HIF-1α protein at
In hypoxia (1–2% O2), the PHD enzyme cannot hydroxylate HIF-1α because oxygen is lacking, VHL cannot bind to the HIF-1α subunit, and therefore, HIF-1α is not degraded by the proteasome [20]. Stabilized HIF-1α is quickly transported to the nucleus to induce the transcription of target genes [20, 29]. In the nucleus, the HIF-1α/HIF-1β heterodimer binds the p300 coactivator [30]. HIF1 and p300 form a complex that binds the double-stranded DNA and promotes transcription. HIF-1α has a plethora of target genes, which encode proteins involved in critical biological processes, such as erythropoiesis, vascular remodeling, metabolism, cell proliferation, cell viability and angiogenesis [9, 10] ( Table 1 ).
Gene name | Gene symbol | Gene function | NCBI Gene ID | Refs |
---|---|---|---|---|
Angiopoietin 1 Angiopoietin 2 |
|
Angiogenesis | 284 285 |
[31] |
BCL2 interacting protein 3 |
|
Apoptosis | 664 | [32, 33] |
BCL2 interacting protein 3-like |
|
Apoptosis | 665 | [33] |
Endothelin-1 |
|
Angiogenesis | 1906 | [34] |
Enolase 1 |
|
Energy metabolism | 2023 | [35] |
Erythropoietin |
|
Proliferation, survival | 2056 | [36] |
Glyceraldehyde-3-phosphate dehydrogenase |
|
Energy metabolism | 2597 | [37] |
Glucose transporter-1 |
|
Energy metabolism | 6513 | [38] |
Hexokinase 1 Hexokinase 2 |
|
Energy metabolism | 3098 3099 |
[39] |
Prolyl 4-hydroxylase subunit alpha 1 |
|
Energy metabolism | 5033 | [40] |
Insulin growth factor 2 |
|
Growth and survival | 3481 | [41] |
Insulin growth factor binding protein 1, 2 and 3 |
|
Growth and survival | 3484 | [41, 42] |
Lactate dehydrogenase A |
|
Energy metabolism | 3939 | [35] |
MAX interactor 1 |
|
Apoptosis, c-Myc activity | 4601 | [43, 44] |
Nitric oxide synthase 2 |
|
Angiogenesis | 4843 | [45] |
Pyruvate kinase M |
|
Energy metabolism | 5315 | [35] |
Pyruvate dehydrogenase kinase 1 |
|
Energy metabolism | 5163 | [46, 47] |
Transforming growth factor beta 3 |
|
Invasion, metastasis, growth, survival | 7043 | [48] |
Tumor protein p53 |
|
Apoptosis | 7157 | [49] |
Twist |
|
Metastasis | 7291 | [50] |
Vascular endothelial growth factor A |
|
Angiogenesis, growth, survival | 7422 | [51] |
Vascular endothelial growth factor receptor 1 |
|
Angiogenesis, growth, survival | 2321 | [52] |
1.3. HIF-1α controls tumor angiogenesis
Angiogenesis is the process of forming new blood vessels from pre-existing ones, which differentiates into a vascular network [53, 54]. Blood vessels supply the body with oxygen, nutrients, and immune surveillance. The extensive growth of veins and their non-physiological remodeling result in multiple illnesses, such as cancer and ischemic and inflammatory diseases (e.g., arthritis, atherosclerosis, and diabetes) [54, 55, 56, 57, 58]. The veins are used as pathways for the migration of cancer cells [54]. Angiogenesis may be adversely affected by infection with pathogenic bacteria. Additionally, angiogenesis is a feature of cancer, as tumor cells induce the process in order to grow and become metastatic [59].
Previous studies have shown a correlation between tumor growth and angiogenesis and have established molecular links between the signaling pathways induced upon infection, gene regulation, and cancer [60, 61, 62, 63]. According to the angiogenesis dogma, a tumor cannot grow more than a few millimeters in diameter, if it does not come in contact with the blood vessels by which it receives enough oxygen [54, 61]. Furthermore, due to the irregular shape and organization of the tumor vasculature, some cells are more than 100 mm away from the blood vessels and they also become hypoxic. The oxygen within the tumor is not static but fluctuates spatially and temporally [64]. Angiogenesis is regulated by molecules that act as “activators” (pro-angiogenic factors) or “inhibitors” (anti-angiogenic factors) [65]. Several studies have shown that the angiogenic activators play an important role in the growth and spread of tumors [66]. Key activators of angiogenesis belong to the family of VEGFs, and their receptors were found expressed in about half of human cancers investigated so far [66].
Importantly, HIF-1α has been shown to control the expression of proangiogenesis regulators, such as VEGF and other growth factors and often activation of their respective pathways feedback to enhance HIF-1α activity [9]. For example, the epidermal growth factors (EGFs) act as angiogenesis activators. The binding of EGF to the epidermal growth factor receptor (EGFR) activates the MAP kinase cascade and also induces the PI3K (phosphatidylinositol 3-kinase)—AKT/PKB (Protein Kinase B) pathway. The PI3K enzyme catalyzes the transfer of a phosphate group, which converts PI phospholipid (phosphatidylinositol) into PI-3P phospholipid (Phosphatidylinositol 3-phosphate). This conversion results in the full activation of the serine/threonine kinase PDK-1 (Phosphoinositide-dependent kinase), which phosphorylates and activates another serine/threonine kinase, known as AKT. PTEN (phosphatase and TENsing homolog), which functions as a kinase with tumor suppressor activity, is a negative regulator of PI3K, which mediates cell proliferation [67]. The protein kinase p70S6 is a target of mTOR. Through phosphorylation, it induces the translation of mRNAs, which encompass a 5′ end rich in pyrimidines. Such sites are found in the HIF-1α mRNA [68].
1.4. Tumor hypoxia, HIF-1α, and the Warburg effect
The hypoxic regions of a tumor are resistant to chemotherapy, exhibit modified metabolism, and often acquire metastatic and invasive properties [69, 70, 71]. Chronic cell proliferation, which appears to correlate with tumor incidence, does not only involve cellular dysfunction but also energy metabolism adjustments through which the organism acquires enough energy by producing ATP, which is used by cancer cells for cell division and growth. In 1924, the Nobelist Otto Warburg first described the preference of cancer cells to convert glucose into lactic acid even in the presence of oxygen [72]. By measuring lactic acid production and oxygen consumption in thin sections from healthy and tumorous rat livers, he concluded that normal liver cells inhibit the production of lactic acid in the presence of oxygen, whereas cancer cells produced lactic acid irrespective of the availability of oxygen [73, 74]. In aerobic conditions, normal cells convert glucose to pyruvic acid via glycolysis in the cytoplasm, and then, pyruvic acid is used in the mitochondria to produce acetyl Coenzyme A (CoA) and carbon dioxide (CO2) during oxidative phosphorylation. In anaerobic conditions, normal cells favor glycolysis, and pyruvic acid is used in the cytoplasm to produce lactic acid. Instead, according to Warburg, cancer cells change their metabolism, and even in the presence of oxygen, glucose enters glycolysis and produces lactic acid. Cancer cells use 10 times more glucose than the amount of the cellular breathing process can use, while the amount of lactic acid produced is two times greater than that produced by healthy cells [73]. This phenomenon is known as the “Warburg effect” or “aerobic glycolysis” [70, 75, 76, 77]. At first sight, this phenomenon seems paradoxical, since aerobic glycolysis produces significantly less energy (4 mol ATP/mol glucose) compared to oxidative phosphorylation (36 mol ATP/mol glucose). Nevertheless, cancer cells exhibit an increased expression of glucose transporters, such as GLUT1, which correlates with enhanced glucose uptake [78, 79, 80]. The feeding of cancer cells with glucose is often associated with oncogene activation and loss-of-function of tumor suppressor genes [78, 79, 81]. The
A series of major discoveries remained as milestones in the field of cancer biology followed Warburg’s observations. These include the purification and cloning of the HIF-1 in 1995 [36], the effects of HIF-1 in cancer progression in mice [93], the description of VHL [94], the identification of the PHD enzymes, and the establishment of the HIF-α subunit prolyl hydroxylation [69]. The area of hypoxia remains an attractive subject for intensive research, although over a century has passed, since it was first taken into account. With the discovery of HIFs, an extremely attractive field of research emerged and novel proteins came into play, such as the glucose regulated proteins (GRPs), oxygen regulated proteins (ORPs), PDGF, interleukin-1α (IL-1α), endothelin-1, VEGF and erythropoietin (EPO) [95, 96, 97, 98, 99, 100]. The characterization of HIF-1 led to the discovery of upstream activators and downstream signals as potential new therapeutic targets. Such targets include the VEGF, fibroblast growth factor (FGF), TGFα, the PI3K/AKT/mTOR and RAS signaling pathways [101]. In addition, reduced oxygen tensions can repress mTOR in the cells similar to the effects of rapamycin. mTOR in hypoxic environments acts as an oxygen sensor and leads to reduced protein translation [102].
The PI3K/AKT pathway inhibits programmed cell death and alters cell proliferation [103]. Loss of PTEN, which is a negative regulator of the pathway, can lead to increased angiogenesis in the case of prostate cancer. This has been associated with the induction of HIF-1α that guides elevated VEGF expression [103, 104]. In colon tumors, transfection of cells with a HIF-1α expression vector resulted in elevated VEGF mRNA levels and increased angiogenesis [90]. The EGF/PI3K/AKT/TOR pathway promotes VEGF and the transcriptional activity of HIF-1α protein in prostate cancer [89]. Chemical inhibitors of PI3K and TOR, the LY294002 and rapamycin, respectively, inhibited growth factor-induced and mitogen-induced secretion of VEGF. This connected the PI3K/PTEN/AKT/TOR pathway with HIF1 and the process of angiogenesis [105]. In the absence of HIF-1α, the development of a tumor is dramatically reduced although not completely stalled [106]. Moreover, HIF-1α is overexpressed in different cancer types, such as colon, breast and lung carcinomas. HIF-1α is also overexpressed in preneoplastic, premalignant adenomas and other intraepithelial neoplasia and also in malignant and metastatic tumors [89]. Therefore, discovery of chemicals that could potentially control the HIF-1α pathway is of major clinical importance.
1.5. HIF-1α and inflammation
Another important aspect of HIF in tissue maintenance is its role in regulating inflammation and innate immunity. HIFs appear to have different functions in different immune cell types. For example, HIF-1α mediates bacterial killing via regulation of pro-inflammatory gene expression in macrophages [107]. On the other hand, in the case of neutrophils, HIF-1α promotes cell survival upon hypoxia and promotes extensive angiogenesis which is regulated by β2-integrin expression. Furthermore, there is a link between the effect of HIFs in immune cells, inflammation, and tumorigenesis [107]. It is known that HIF-1α is regulated by the availability of oxygen. Interestingly, not only hypoxia but also bacterial products, such as cytokines and growth factors, induce HIF-1α. Inflammatory cytokines, such as tumor necrosis factor a (TNF-α) and interleukin-1β (IL-1β), induce HIF-1α transcription. TNF-α induces HIF transcription and the Nuclear Factor-kappa B (NF-κB) pathway is needed for stabilization of the protein [108, 109]. In the case of IL-1β, the stability of HIF is promoted by the activation of NF-kB activity and the inhibition of VHL function [110]. There is an important crosstalk between NF-kB and HIF upon inflammation and cancer [111]. NF-kB is activated in inflammatory conditions, including cancer, and the activation of the pathway is a characteristic of inflammatory disease [59]. Its role in malignant situations is controversial such that it can act both as a tumor promoter and as a tumor suppressor [112]. Its activated form is implicated in excessive cell proliferation, metastasis, inhibition of apoptosis and angiogenesis [112]. Importantly, cells expressing wild-type p53 undergo apoptosis in hypoxic conditions, in contrast to the mutant p53 cells that are resistant to apoptosis. These results reveal that HIF-1α can promote cell proliferation and thus tumorigenesis by inhibiting apoptosis [113]. The chemokine interleukin-8 (IL-8) [114] and the VEGF [115] NF-kB target genes promote angiogenesis. Importantly, these are also targets of HIF-1α [116, 117], revealing that there is a crosstalk between NF-kB and HIF-1α. This crosstalk is bi-directional, because although NF-kB promotes the activation of HIF, HIF restricts the transcriptional activity of NF-kB [117]. Inflammation promotes NF-kB activity, which leads to tumorigenesis [118]. Not only NF-kB, but also other transcription factors (e.g. STAT3) can induce HIF [119]. PHDs antagonize NF-kB in different tumor cells [120, 121, 122]. In colorectal cancer, NF-kB promotes tumorigenesis. Different signaling pathways drive its oncogenic role. These pathways regulate the production of ROS, the activation of pro-inflammatory cytokines, the uncontrolled cell proliferation, migration, metastasis and angiogenesis [123]. The absence of NF-kB has a negative effect on tumor progression in mouse models of colorectal cancer [124]. ROS affect the hydroxylation of HIF-1α and, thus, modify its activity [125, 126]. Specific defects, not necessarily mitochondrial defects, that restrict the consumption of oxygen, result in enhanced prolyl-hydroxylation accompanied with reduced HIF levels [125, 127].
The induction of HIF by such inflammatory cytokines indicates that HIF has a crucial role in inflammatory responses. Apart from inflammatory cytokines, various signaling pathways seem to also have important roles in the stimulation of HIF. Such pathways include PHDs [128], NF-κB [129, 130, 131], MAPKs [130], and ROS [129]. In addition, ROS are released by the mitochondria as a cause of low oxygen tensions, and they can control transcriptional and posttranslational events [132]. Another important crosstalk in colorectal cancer is that between HIF-1α, β-catenin and APC: when repressed under insufficient oxygen levels, APC can lead to activation of the Wnt/β catening signaling and increased proliferation that drives tumorigenesis [133]. Interestingly, NF-kB is regulated by Wnt/β-catenin [134].
2. The HIF-1α pathway in Drosophila melanogaster
2.1. The HIF-1α pathway is conserved in Drosophila
The
Sima has a molecular weight of 180 kDa, is larger compared to the mammalian HIF-1α, and bears 45% similarity in the PAS domain and 63% in the bHLH domain with its human homolog (
Figure 1
) [141, 142]. The single prolyl-4-hydroxylase (PHD) enzyme homolog in
Gene name | Gene symbol | Human homolog | Gene function | NCBI Gene ID | Refs |
---|---|---|---|---|---|
|
|
|
Tracheal development, cell migration | 42356 | [144] |
|
|
|
Tracheal development, cell migration | 39564 | [144] |
|
|
|
Energy metabolism | 45880 | [145] |
|
|
|
Energy metabolism | 40633 | [146] |
|
|
|
Heat response, defense response | 37068 | [147] |
2.2. HIF-1α/Sima controls remodeling of the tracheal gas-transporting tubes
In
Remarkably,
Interestingly, the embryonic and larval fly trachea encompasses specialized cells, which extend cytoplasmic processes to carry oxygen to the tissue. These cells, known as tracheal terminal cells, are very similar to the tip cells of the mammalian blood vessels; they are plastics and they respond to hypoxia by extending cytoplasmic tubular processes, the terminal branches, toward the hypoxic tissue [148]. The sprouting and growth of the terminal branches are carefully adjusted according to the needs of tissue in oxygen, just as in the case of sprouting angiogenesis in mammals. Hypoxia induces terminal branching, whereas hyperoxia (increased oxygen supply) suppresses the formation of terminal branches [148, 168]. Hypoxia induces the expression of
2.3. HIF-1α/Sima and growth control in Drosophila
Insects have a mechanism of body size plasticity. Oxygen sensing has a major role in this mechanism. Hypoxia causes a reduction of body size in the fruit fly
Over the last decade, many scientists tried to address the role of HIF in cell growth and cell size control. Overexpression of
It is firmly established that insulin growth factors and components of the insulin pathway upregulate the HIF-1α protein, thus promoting the expression of hypoxia-sensitive genes [174]. The PI3K/Akt/TOR signaling pathway is directed by insulin to induce the transcription of
2.4. Other functions of HIF-1α/Sima in Drosophila
2.4.1. Epithelial cell migration
A 2010 study dealt with the role of Sima in the rate of cell migration and invasion of the ovarian border cells in
2.4.2. Blood cell differentiation
A recent study dealing with the role of HIF-1α in
2.5. Upstream regulators of HIF-1α/Sima in hypoxia
A genome-wide RNAi screen was deployed in
Further work on Sima regulators has uncovered several modifiers of Sima function in hypoxia in
2.6. HIF-1α/Sima in Drosophila tumorigenesis
The connection between metabolism deregulation and tumorigenesis is already established [187] and various signaling pathways with crucial roles in cancer progression regulate the expression of metabolic genes encoding key glycolytic enzymes [78, 79, 188]. In addition, the transcription factor HIF-1α controls expression of a number of genes involved in different hallmarks of cancer including modifiers of cellular metabolism that facilitate neoplasia [189]. A recent study in
An independent study also assessed Sima expression, as well as induction of tracheogenesis in
3. Conclusions and future perspectives
This book chapter discusses our current knowledge on HIFs and their major roles in development, physiology and disease pathology, using examples of studies in the model organism
The HIF-1α transcription factor has been extensively studied in mammals and in a variety of model organisms due to its highly conserved sequence and function (
Figure 1
). The extensive literature on the
The contribution of HIF-1α/Sima in epithelial tumorigenesis and tracheogenesis in
Undoubtedly,
Abbreviation
ago1 | argonaute 1 |
Ago | Archipelago |
ARNT2 | aryl hydrocarbon receptor nuclear translocator 2 |
ARNT3 | aryl hydrocarbon receptor nuclear translocator 3 |
ATP | adenosine tri-phosphate |
bHLH-PAS | basic-Helix-Loop-Helix-Per/ARNT/Sim |
bnl | branchless |
btl | breathless |
Cdk4 | cyclin-dependent protein kinase 4 |
CoA | acetyl coenzyme A |
CO2 | carbon di oxide |
Cul2 | cullin 2 |
dlg | discs large |
dMsi | Drosophila Mushashi |
EGFR | epidermal growth factor receptor |
EGFs | epidermal growth factors |
EPO | erythropoietin |
fga | fatiga |
FGF | fibroblast growth factor |
GLUTs | glucose transporters |
GLUT1 | glucose transporter 1 |
GRPs | glucose regulated proteins |
HIFs | hypoxia-inducible factors |
HIF1 | hypoxia-inducible factor 1 |
HIF-1α | hypoxia-inducible factor-1α |
HIF-1β | hypoxia-inducible factor-1β |
HIF-2α | hypoxia-inducible factor-2α |
HIF-3α | hypoxia-inducible factor-3α |
hRafact | human Raf gain-of-function |
HREs | hypoxia-response elements |
ID | inhibitory domain |
IGF-I | insulin growth factor I |
ILP | insulin-like peptide |
IL-1α | interleukin-1α |
IL-1β | interleukin-1β |
IL-8 | interleukin-8 |
InR | insulin receptor |
LDH | lactate dehydrogenase |
LDHA | lactate dehydrogenase A |
lgl | lethal giant larvae |
lglKD | lgl knockdown |
miR | microRNA |
Msi | Musashi |
NF-κB | nuclear factor-kappa B |
Nfl | Notch full-length |
NLS-C | carboxy-terminal Nuclear Localization Signals |
NLS-N | amino-terminal Nuclear Localization Signals |
NO | nitric oxide |
NOS | nitric oxide synthase |
NOS1 | nitric oxide synthase1 |
ORPs | oxygen regulated Proteins |
OXPHOS | oxidative phosphorylation |
O2 | oxygen |
PcG | polycomb group |
PDGF-β | platelet-derived growth factor beta |
PDK1 | pyruvate dehydrogenase kinase 1 |
PDK-1 | phosphoinositide-dependent kinase 1 |
PHD | prolyl-4-hydroxylase |
PI | phosphatidylinositol |
PI3K | phosphatidylinositol 3-kinase |
PI3Kact | PI3K activated |
PI-3P | phosphatidylinositol 3-phosphate |
PKB | protein Kinase B |
Pro | proline |
PSTD | Proline-Serine–Threonine-rich protein stabilization Domain |
PTEN | phosphatase and TENsing homolog |
Pvr | PDGF/VEGF-receptor |
Pxn | peroxidasin |
Rbx1 | ring box protein 1 |
RNAi | RNA interference |
ROSs | reactive oxygen species |
scrib | scribble |
sima | similar |
Slbo | slow border cells |
TAD-C | carboxy-terminal transactivation domains |
TAD-N | amino-terminal transactivation domains |
TGF-α | transforming growth factor alpha |
tgo | tango |
TNF-α | tumor necrosis factor α |
trh | trachealess |
VEGF | vascular endothelial growth factor |
VHL | von Hippel-Lindau |
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