Abstract
Multiple cell cycle regulatory proteins play an important role in oncogenesis. Cancer cells may arise from dysregulation of various genes involved in the regulation of the cell cycle. In addition, cyclin-dependent kinase inhibitors are regarded as key regulators for cancer cell proliferation. Accordingly, permission of impaired cells by cell cycle checkpoints suppresses carcinogenesis. P53, a multifunctional protein, controls G1-S transition, which is the strongest tumor suppressor involved in the regulation of cell cycle. The p53 is stimulated by cellular stress like oxidative stress. Upon activation, p53 leads to cell cycle arrest and promotes DNA repair; otherwise, it induces apoptosis. One of the target effectors of p53 is the phosphatase and tensin homolog deleted on chromosome 10 (PTEN). The tumor suppressor PTEN is a dual-specificity phosphatase which has protein phosphatase activity and lipid phosphatase activity that antagonizes PI3K/AKT activity. The PI3K/AKT cell survival pathway is shown as regulator of cell proliferation. The p53 cooperates with PTEN and might be an essential barrier in development of cancers. BRCA1 plays an important role in DNA repair processes related to maintenance of genomic integrity and control of cell growth. The inactivation of these tumor suppressor proteins confers a growth advantage of cancer. This chapter summarizes the function of several tumor suppressors in the cell cycle regulation.
Keywords
- p53
- PTEN
- BRCA1
- AKT
- MDM2
- p21WAF1
- protein interaction
- protein expression
- cell signaling
- DNA repair
- cell cycle regulation
1. Introduction
Mechanisms of cell cycle are predominantly controlled by p53 tumor suppressor [1, 2]. The p53 transcription factor can bring G1 arrest of the cell cycle by transactivating several downstream molecules [3, 4], which regulates various signaling pathways involved in the cellular response to genome stress and DNA damage. Through the stress-induced activation, p53 triggers the expression of target genes that protect the genetic reliability of cells [5]. Germinal mutations of the
2. Characteristics of p53 , PTEN , and BRCA1
The
3. Relationship among PTEN, p53, BRCA1, and MDM2
The PTEN and p53 complex augments the p53-DNA binding and the transcriptional action [41], which may upregulate the expression of PTEN itself and p21WAF1, which is a key molecule involved in cell cycle arrest [42]. Indeed, a superior function of p53 is to work as a transcription factor by attaching to the definite DNA consensus sequence on the p53 responsive genes. Consequently, p53 indirectly inhibits production of PIP3 by inducing the expression of this PTEN. In addition, PTEN associates with p53 and regulates the transcriptional activity of p53 by modulating its DNA binding. PTEN is also required for the maintenance of p53 acetylation [43], which is essential for target gene transcription. An adjacent function of PTEN as a tumor suppressor is accomplished through the stabilization of the p53 protein. PTEN and p53 form a complex in the nucleus under hypoxic conditions [44]. Nuclear PTEN is sufficient to reduce cancer progression in a p53-dependent manner [45]. In addition, the nuclear PTEN seems to mediate DNA damage repair through modulating the activity of DNA repair molecules. The PI3K-dependent activation of AKT indirectly leads to the inhibition of p53 functions by activating another tumor suppressor MDM2 [46]. Activation of AKT has the potential of reducing the p53-mediated cell cycle checkpoints through phosphorylation and appropriation of p21WAF1 [47]. By the way, several PI3K inhibitors favorably reduce proliferation of BRCA1-defective breast cancer cells. For example, BEZ235 inhibits not only PI3K/mTOR but also ATM/ATR [48, 49]. It is possible that ATM pathways are involved in upregulation of the PI3K/AKT pathway in BRCA1-defective cancer cells. In contrast, BRCA1 may regulate the PI3K/AKT pathway by acting on upstream kinases of AKT. Overexpression of wild-type BRCA1 could further reduce basal phosphorylation of AKT levels in MCF7 cells [10, 50]. In addition, reduced levels of PTEN are associated with radio-resistance which can be suppressed by the ectopic PTEN expression [51, 52].
MDM2 controls carcinogenesis, whose mRNA level is also transcriptionally regulated by p53 in response to DNA damage [53]. MDM2 protein and subcellular localization are post-translationally modulated by AKT [53]. Besides inhibiting the PI3K/AKT signaling, PTEN also promotes translocation of the MDM2 into the nucleus. Furthermore, PTEN modulates
4. Involvement of the p53-PTEN-MDM2-BRCA1 loop in cell cycle regulation
The levels of p53 could vary and is positively related to the amount of DNA damage [61]. Low levels of p53 may induce cell cycle arrest, whereas high levels of p53 may induce apoptosis. On the other hand, growth factor-activated AKT signaling supports progression of cell cycle by acting on several factors involved in the G1/S or G2/M cell cycle transitions. Because the ability of p53 to induce cell cycle arrest and/or cell apoptosis can be provoked by cell survival signals including the AKT pathway, the cell growth signal circuitously leads to the inhibition of p53 by triggering its negative regulators [62]. The p53 protein also regulates BRCA1 transcription both in vitro and in vivo, and BRCA1 participates in p53 accumulation after irradiation through regulation of its phosphorylation and MDM2 expression [63]. MDM2 can act as a modifier of BRCA1 mutant and may accelerate breast and ovarian carcinogenesis [64]. In addition, p53 and PTEN are known to interact and to regulate each other at the transcription as well as protein level, which could be at the important control machinery for switching between survival and death. Given the ability of PTEN to stabilize p53 protein through provoking the AKT-MDM2 complex or by increasing p53 acetylation, the decreased p53 activity in PTEN-lacking tumor cells could be plausible. PTEN and BRCA1 may be regulated and interact with each other at multiple levels including transcription, protein modulation, and protein stability. Therefore, the p53-PTEN-MDM2-BRCA1 loop in cell cycle regulation now becomes dominant (Figure 3). These cross talks are frequently a combination of reciprocally antagonistic pathways, which may often serve as an additional regulatory effect on the expression of key genes involved in cell cycle and carcinogenesis. Interestingly, genistein, which is a soy isoflavone, brings regulation between PTEN and p53 to support cell cycle arrest [65]. Genistein induces PTEN expression and nuclear accumulation, which elicits a sequence of PTEN-dependent nuclear p53 accumulation and recruitment of the PTEN/p53 complex to the p53 binding sites [65], then attenuates expression of cell proliferative genes [65]. In addition, genistein inhibits cell proliferation and induces cell apoptosis more proficiently in BRCA1-mutant cells than in cells expressing wild-type BRCA1 protein [66]. BRCA1-mutant breast cancer cells are highly sensitive to genistein treatment, and AKT could be genistein targets in these cells [66]. Accordingly, genetic variants in the molecules of p53, PTEN, BRCA1, and MDM2 may play roles in tumor suppressor network mediating a susceptibility to cancer. Remarkably, it has also been presented that zinc deficiency modulates the p53-PTEN-BRCA1-MDM2 signaling network in normal cells [67].
5. Perspective
In unstressed cells, p53 may be regularly kept at low levels by its negative regulator MDM2. This feedback loop among the p53-PTEN-MDM2-BRCA1 may function for the accurate regulation of the DNA repair and cell cycle (Figure 3). When stressed, the tumor suppressor p53 predominantly induces cell cycle arrest or apoptosis in the response to DNA damage. Indeed, the regulation is crucial for the effective design of novel cancer therapeutics. Further mechanistic studies are needed in order to understand the exact molecular mechanisms for the effective treatment of cancers with the functional alterations in the cellular signaling loop. Targets within this pathway could provide strategies therapeutically valuable for several cancer treatments. It is important to investigate the linkage among the molecules, and elucidation of interaction-specific functions may provide insight into regulatory aspects of these tumor suppressors as well as opportunities for therapeutic intervention. Such molecular interactions may sustain the biological plausibility that the combination of variants of the p53-PTEN-MDM2-BRCA1 network could result in more comprehensive. Genetic analysis for germline mutations in these key genes allows for the identification of characters at increased risk of cancers. However, they may be regulated and interact with each other at multiple levels including transcription, protein modulation, and protein stability. Obviously, understanding the regulation is crucial for the effective design of novel cancer prevention and therapeutics. Further studies are needed to understand molecular mechanisms in more detail.
6. Abbreviations
ATM: ataxia telangiectasia-mutated
HDM2: human homolog of MDM2
LOH: Loss of heterozygosity
MDM2: murine double minute 2
NEDL1: NEDD4-like ubiquitin protein ligase-1
NF-
NLS: Nuclear Localization Signal
mTOR: mammalian target of rapamycin
PDZ: PSD-95, DLG1, and ZO-1
PEST: proline, glutamic acid, serine and threonine
PTEN: phosphatase and tensin homolog deleted on chromosome 10
PIP2: phosphatidylinositol 4,5- bisphosphate
PIP3: phosphatidylinositol 3,4,5-triphosphate
PI3K: phosphoinositide-3 kinase
RING: really interesting new gene finger domain
RTK: receptor tyrosine kinase
ROS: reactive oxidative species
Acknowledgments
This work was supported by JSPS KAKENHI Grant Number 25560050, 26-12035, 24240098.
References
- 1.
Xia L, Paik A, Li JJ (2004). p53 activation in chronic radiation-treated breast cancer cells: regulation of MDM2/p14ARF. Cancer Res. 64:221–228. - 2.
Calcagno DQ, Freitas VM, Leal MF, de Souza CR, Demachki S, Montenegro R, Assumpção PP, Khayat AS, Smith Mde A, dos Santos AK, Burbano RR (2013). MYC, FBXW7 and TP53 copy number variation and expression in gastric cancer. BMC Gastroenterol. 13:141. - 3.
Kuribayashi K, El-Deiry WS (2008). Regulation of programmed cell death by the p53 pathway. Adv Exp Med Biol. 615:201–221. - 4.
Matsumoto M, Furihata M, Ohtsuki Y (2006). Posttranslational phosphorylation of mutant p53protein in tumor development. Med Mol Morphol. 39(2):79–87. - 5.
Frum RA, Grossman SR (2014). Mechanisms of mutant p53 stabilization in cancer. Subcell Biochem. 85:187–197. - 6.
Merino D, Malkin D (2014). p53 and hereditary cancer. Subcell Biochem. 85:1–16. - 7.
Minami A, Nakanishi A, Ogura Y, Kitagishi Y, Matsuda S (2014). Connection between tumor suppressor BRCA1 and PTEN in damaged DNA repair. Front Oncol. 4:318. - 8.
Yang X, Zhang Z, Wang X, Wang Y, Zhang X, Lu H, Wang SL (2013). Cytochrome P450 2A13 enhances the sensitivity of human bronchial epithelial cells to aflatoxin B1-induced DNA damage. Toxicol Appl Pharmacol. 270:114–121. - 9.
Zhou C, Smith JL, Liu J (2003). Role of BRCA1 in cellular resistance to paclitaxel and ionizing radiation in an ovarian cancer cell line carrying a defective BRCA1. Oncogene. 22:2396–2404. - 10.
Yi YW, Kang HJ, Kim HJ, Hwang JS, Wang A, Bae I (2013). Inhibition of constitutively activated phosphoinositide 3-kinase/AKT pathway enhances antitumor activity of chemotherapeutic agents in breast cancer susceptibility gene 1-defective breast cancer cells. Mol Carcinog. 52:667–675. - 11.
Carnero A, Paramio JM (2014). The PTEN/PI3K/AKT pathway in vivo, cancer mouse models. Front Oncol. 4:252. - 12.
Spinelli L, Black FM, Berg JN, Eickholt BJ, Leslie NR (2015). Functionally distinct groups of inherited PTEN mutations in autism and tumour syndromes. J Med Genet. 52:128–134. - 13.
Yu X, Si J, Zhang Y, Dewille JW (2010). CCAAT/enhancer binding protein-delta (C/EBP-delta) regulates cell growth, migration and differentiation. Cancer Cell Int. 10:48. - 14.
Kim E, Giese A, Deppert W (2009). Wild-type p53 in cancer cells: when a guardian turns into a blackguard. Biochem Pharmacol. 77:11–20. - 15.
Tomkova K, Tomka M, Zajac V (2008). Contribution of p53, p63, and p73 to the developmental diseases and cancer. Neoplasma. 55:177–181. - 16.
Cheok CF, Lane DP (2012). Seeking synergy in p53transcriptional activation for cancer therapy. Discov Med. 14:263–271. - 17.
Wade M, Li YC, Wahl GM (2013). MDM2, MDMX and p53 in oncogenesis and cancer therapy. Nat Rev Cancer. 13:83–96. - 18.
Zhang Q, Zeng SX, Lu H (2014). Targeting p53-MDM2-MDMX loop for cancer therapy. Subcell Biochem. 85:281–319. - 19.
Carracedo A, Alimonti A, Pandolfi PP (2011). PTEN level in tumor suppression: how much is too little? Cancer Res. 71:629–633. - 20.
Eng C (2003). PTEN: one gene, many syndromes. Hum Mutat. 22:183–198. - 21.
Sotelo NS, Schepens JT, Valiente M, Hendriks WJ, Pulido R (2015). PTEN-PDZ domain interactions: binding of PTEN to PDZ domains of PTPN13. Methods. 77–78:147–156. - 22.
Maehama T, Taylor GS, Dixon JE (2001). PTEN and myotubularin: novel phosphoinositide phosphatases. Annu Rev Biochem. 70:247–279. - 23.
Miao B, Skidan I, Yang J, Lugovskoy A, Reibarkh M, Long K, Brazell T, Durugkar KA, Maki J, Ramana CV, Schaffhausen B, Wagner G, Torchilin V, Yuan J, Degterev A (2010). Small molecule inhibition of phosphatidylinositol-3,4,5-triphosphate (PIP3) binding to pleckstrin homology domains. Proc Natl Acad Sci U S A. 107:20126–20131. - 24.
Fresno Vara JA, Casado E, de Castro J, Cejas P, Belda-Iniesta C, González-Barón M (2004). PI3K/Akt signalling pathway and cancer. Cancer Treat Rev. 30:193–204. - 25.
Anai M, Shojima N, Katagiri H, Ogihara T, Sakoda H, Onishi Y, Ono H, Fujishiro M, Fukushima Y, Horike N, Viana A, Kikuchi M, Noguchi N, Takahashi S, Takata K, Oka Y, Uchijima Y, Kurihara H, Asano T (2005). A novel protein kinase B (PKB)/AKT-binding protein enhances PKB kinase activity and regulates DNA synthesis. J Biol Chem. 280:18525–18535. - 26.
Petrella BL, Brinckerhoff CE (2009). PTEN suppression of YY1 induces HIF-2 activity in von-Hippel-Lindau-null renal-cell carcinoma. Cancer Biol Ther. 8:1389–1401. - 27.
Yamamoto M, Tamakawa S, Yoshie M, Yaginuma Y, Ogawa K (2006). Neoplastic hepatocyte growth associated with cyclin D1 redistribution from the cytoplasm to the nucleus in mouse hepatocarcinogenesis. Mol Carcinog. 45:901–913. - 28.
Hennenlotter J, Ohneseit PA, Simon P, Merseburger AS, Serth J, Kuehs U, Kramer M, Hartmann JT, Stenzl A, Kuczyk MA (2008). PTEN and p27Kip1 are not downregulated in the majority of renal cell carcinomas – implications for Akt activation. Oncol Rep. 19:1141–1147. - 29.
Tamguney T, Stokoe D (2007). New insights into PTEN. J Cell Sci. 120:4071–4079. - 30.
Shi Y, Paluch BE, Wang X, Jiang X (2012). PTEN at a glance. J Cell Sci. 125:4687–4692. - 31.
Yang Y, Swaminathan S, Martin BK, Sharan SK (2003). Aberrant splicing induced by missense mutations in BRCA1: clues from a humanized mouse model. Hum Mol Genet. 12:2121–2131. - 32.
Miyamoto K (2014). Structural model of ubiquitin transfer onto an artificial RING finger as an E3 ligase. Sci Rep. 4:6574. - 33.
Bahassi el M, Penner CG, Robbins SB, Tichy E, Feliciano E, Yin M, Liang L, Deng L, Tischfield JA, Stambrook PJ (2007). The breast cancer susceptibility allele CHEK2*1100delC promotes genomic instability in a knock-in mouse model. Mutat Res. 616:201–209. - 34.
Brew CT, Aronchik I, Hsu JC, Sheen JH, Dickson RB, Bjeldanes LF, Firestone GL (2006). Indole-3-carbinol activates the ATM signaling pathway independent of DNA damage to stabilize p53 and induce G1 arrest of human mammary epithelial cells. Int J Cancer. 118:857–868. - 35.
Li J, Stern DF (2005). DNA damage regulates Chk2 association with chromatin. J Biol Chem. 280:37948–37956. - 36.
Lane TF (2004). BRCA1 and transcription. Cancer Biol Ther. 3:528–533. - 37.
Yu X, Chini CC, He M, Mer G, Chen J (2003). The BRCT domain is a phospho-protein binding domain. Science. 302:639–642. - 38.
Fourati A, Louchez MM, Fournier J, Gamoudi A, Rahal K, El May MV, El May A, Revillion F, Peyrat JP (2014). Screening for common mutations in BRCA1 and BRCA2 genes: interest in genetic testing of Tunisian families with breast and/or ovarian cancer. Bull Cancer. 101:E36–E40. - 39.
Jhanwar-Uniyal M (2003). BRCA1 in cancer, cell cycle and genomic stability. Front Biosci. 8:s1107–s1117. - 40.
Krämer A, Lukas J, Bartek J (2004). Checking out the centrosome. Cell Cycle. 3:1390–1393. - 41.
Freeman DJ, Li AG, Wei G, Li HH, Kertesz N, Lesche R, Whale AD, Martinez-Diaz H, Rozengurt N, Cardiff RD, Liu X, Wu H (2003). PTEN tumor suppressor regulates p53 protein levels and activity through phosphatase-dependent and -independent mechanisms. Cancer Cell. 3:117–130. - 42.
Todorova VK, Kaufmann Y, Luo S, Klimberg VS (2006). Modulation of p53 and c-myc in DMBA-induced mammary tumors by oral glutamine. Nutr Cancer. 54:263–273. - 43.
Li AG, Piluso LG, Cai X, Wei G, Sellers WR, Liu X (2006). Mechanistic insights into maintenance of high p53acetylation by PTEN. Mol Cell. 23:575–587. - 44.
Eitel JA, Bijangi-Vishehsaraei K, Saadatzadeh MR, Bhavsar JR, Murphy MP, Pollok KE, Mayo LD (2009). PTEN and p53 are required for hypoxia induced expression of maspin in glioblastoma cells. Cell Cycle. 8:896–901. - 45.
Chang CJ, Mulholland DJ, Valamehr B, Mosessian S, Sellers WR, Wu H (2008). PTEN nuclear localization is regulated by oxidative stress and mediates p53-dependent tumor suppression. Mol Cell Biol. 28:3281–3289. - 46.
Fenouille N, Puissant A, Tichet M, Zimniak G, Abbe P, Mallavialle A, Rocchi S, Ortonne JP, Deckert M, Ballotti R, Tartare-Deckert S (2011). SPARC functions as an anti-stress factor by inactivating p53 through Akt-mediated MDM2 phosphorylation to promote melanoma cell survival. Oncogene. 30:4887–4900. - 47.
Mitsuuchi Y, Johnson SW, Selvakumaran M, Williams SJ, Hamilton TC, Testa JR (2000). The phosphatidylinositol 3-kinase/AKT signal transduction pathway plays a critical role in the expression of p21WAF1/CIP1/SDI1 induced by cisplatin and paclitaxel. Cancer Res. 60:5390–5394. - 48.
Sun Z, Li Q, Zhang S, Chen J, Huang L, Ren J, Chang Y, Liang Y, Wu G (2015). NVP-BEZ235 overcomes gefitinib-acquired resistance by down-regulating PI3K/AKT/mTOR phosphorylation. Onco Targets Ther. 8:269–277. - 49.
Fiskus W, Verstovsek S, Manshouri T, Smith JE, Peth K, Abhyankar S, McGuirk J, Bhalla KN (2013). Dual PI3K/AKT/mTOR inhibitor BEZ235 synergistically enhances the activity of JAK2 inhibitor against cultured and primary human myeloproliferative neoplasm cells. Mol Cancer Ther. 12:577–588. - 50.
Nair HB, Perla RP, Kirma NB, Krishnegowda NK, Ganapathy M, Rajhans R, Nair SS, Saikumar P, Vadlamudi RK, Tekmal RR (2012). Estrogen receptor-beta mediates the protective effects of aromatase induction in the MMTV-Her-2/neu x aromatase double transgenic mice. Horm Cancer. 3:26–36. - 51.
Ettl T, Viale-Bouroncle S, Hautmann MG, Gosau M, Kölbl O, Reichert TE, Morsczeck C (2015). AKT and MET signalling mediates antiapoptotic radioresistance in head neck cancer cell lines. Oral Oncol. 51:158–163. - 52.
Tomioka A, Tanaka M, De Velasco MA, Anai S, Takada S, Kushibiki T, Tabata Y, Rosser CJ, Uemura H, Hirao Y (2008). Delivery of PTEN via a novel gene microcapsule sensitizes prostate cancer cells to irradiation. Mol Cancer Ther. 7:1864–1870. - 53.
Chang CJ, Freeman DJ, Wu H (2004). PTEN regulates Mdm2 expression through the P1 promoter. J Biol Chem. 279:29841–29848. - 54.
Reed SM, Hagen J, Tompkins VS, Thies K, Quelle FW, Quelle DE (2014). Nuclear interactor of ARF and Mdm2 regulates multiple pathways to activate p53. Cell Cycle. 13:1288–1298. - 55.
Mitra AK, Jia G, Gangahar DM, Agrawal DK (2009). Temporal PTEN inactivation causes proliferation of saphenous vein smooth muscle cells of human CABG conduits. J Cell Mol Med. 13:177–187. - 56.
Jin L, Li C, Xu Y, Wang L, Liu J, Wang D, Hong C, Jiang Z, Ma Y, Chen Q, Yu F (2013). Epigallocatechin gallate promotes p53 accumulation and activity via the inhibition of MDM2-mediated p53 ubiquitination in human lung cancer cells. Oncol Rep. 29:1983–1990. - 57.
Nadeau G, Boufaied N, Moisan A, Lemieux KM, Cayanan C, Monteiro AN, Gaudreau L (2000). BRCA1 can stimulate gene transcription by a unique mechanism. EMBO Rep. 1:260–265. - 58.
Caldon CE (2014). Estrogen signaling and the DNA damage response in hormone dependent breast cancers. Front Oncol. 4:106. - 59.
Zhan Q (2005). Gadd45a, a p53- and BRCA1-regulated stress protein, in cellular response to DNA damage. Mutat Res. 569:133–143. - 60.
Chai YL, Cui J, Shao N, Shyam E, Reddy P, Rao VN (1999). The second BRCT domain of BRCA1 proteins interacts with p53 and stimulates transcription from the p21WAF1/CIP1 promoter. Oncogene. 18:263–268. - 61.
Hrubá E, Trilecová L, Marvanová S, Krcmár P, Vykopalová L, Milcová A, Líbalová H, Topinka J, Starsíchová A, Soucek K, Vondrácek J, Machala M (2010). Genotoxic polycyclic aromatic hydrocarbons fail to induce the p53-dependent DNA damage response, apoptosis or cell-cycle arrest in human prostate carcinoma LNCaP cells. Toxicol Lett. 197:227–235. - 62.
Collado M, Medema RH, Garcia-Cao I, Dubuisson ML, Barradas M, Glassford J, Rivas C, Burgering BM, Serrano M, Lam EW (2000). Inhibition of the phosphoinositide 3-kinase pathway induces a senescence-like arrest mediated by p27Kip1. J Biol Chem. 275:21960–21968. - 63.
Xu X, Qiao W, Linke SP, Cao L, Li WM, Furth PA, Harris CC, Deng CX (2001). Genetic interactions between tumor suppressors Brca1 and p53 in apoptosis, cell cycle and tumorigenesis. Nat Genet. 28:266–271. - 64.
Yarden RI, Friedman E, Metsuyanim S, Olender T, Ben-Asher E, Papa MZ (2008). MDM2 SNP309 accelerates breast and ovarian carcinogenesis in BRCA1 and BRCA2 carriers of Jewish-Ashkenazi descent. Breast Cancer Res Treat. 111:497–504. - 65.
Park CE, Yun H, Lee EB, Min BI, Bae H, Choe W, Kang I, Kim SS, Ha J (2010). The antioxidant effects of genistein are associated with AMP-activated protein kinase activation and PTEN induction in prostate cancer cells. J Med Food. 13:815–820. - 66.
Privat M, Aubel C, Arnould S, Communal Y, Ferrara M, Bignon YJ (2010). AKT and p21 WAF1/CIP1 as potential genistein targets in BRCA1-mutant human breast cancer cell lines. Anticancer Res. 30:2049–2054. - 67.
Li J, Tan J, Zhuang L, Banerjee B, Yang X, Chau JF, Lee PL, Hande MP, Li B, Yu Q (2007). Ribosomal protein S27-like, a p53-inducible modulator of cell fate in response to genotoxic stress. Cancer Res. 67:11317–11326.