Functions of p53 in pluripotent stem cells

Abstract

Pluripotent stem cells (PSCs) are capable of unlimited self-renewal in culture and differentiation into all functional cell types in the body, and thus hold great promise for regenerative medicine. To achieve their clinical potential, it is critical for PSCs to maintain genomic stability during the extended proliferation. The critical tumor suppressor p53 is required to maintain genomic stability of mammalian cells. In response to DNA damage or oncogenic stress, p53 plays multiple roles in maintaining genomic stability of somatic cells by inducing cell cycle arrest, apoptosis, and senescence to prevent the passage of genetic mutations to the daughter cells. p53 is also required to maintain the genomic stability of PSCs. However, in response to the genotoxic stresses, a primary role of p53 in PSCs is to induce the differentiation of PSCs and inhibit pluripotency, providing mechanisms to maintain the genomic stability of the self-renewing PSCs. In addition, the roles of p53 in cellular metabolism might also contribute to genomic stability of PSCs by limiting oxidative stress. In summary, the elucidation of the roles of p53 in PSCs will be a prerequisite for developing safe PSC-based cell therapy.

Keywords

p53 / embryonic stem cells / induced pluripotent stem cells / genetic stability / metabolism

References

[1] Aladjem MI, Spike BT, Rodewald LW, Hope TJ, Klemm M, Jaenisch R, Wahl GM (1998) ES cells do not activate p53-dependent stress responses and undergo p53-independent apoptosis in response to DNA damage. Curr Biol 8:145–155

[2] Angelos MG, Kaufman DS (2015) Pluripotent stem cell applications for regenerative medicine. Curr Opin Organ Transplant 20:663–670

[3] Banito A, Rashid ST, Acosta JC, Li S, Pereira CF, Geti I, Pinho S, Silva JC, Azuara V, Walsh M (2009) Senescence impairs successful reprogramming to pluripotent stem cells. Genes Dev 23:2134–2139

[4] Barlev NA, Liu L, Chehab NH, Mansfield K, Harris KG, Halazonetis TD, Berger SL (2001) Acetylation of p53 activates transcription through recruitment of coactivators/histone acetyltransferases. Mol Cell 8:1243–1254

[5] Blanpain C, Simons BD (2013) Unravelling stem cell dynamics by lineage tracing. Nat Rev Mol Cell Biol 14:489–502

[6] Boland MJ, Hazen JL, Nazor KL, Rodriguez AR, Gifford W, Martin G,Kupriyanov S, Baldwin KK (2009) Adult mice generated from induced pluripotent stem cells. Nature 461:91–94

[7] Boulting GL, Kiskinis E, Croft GF, Amoroso MW, Oakley DH, Wainger BJ, Williams DJ, Kahler DJ, Yamaki M, Davidow L (2011) A functionally characterized test set of human induced pluripotent stem cells. Nat Biotechnol 29:279–286

[8] Brooks CL, Gu W (2006) p53 ubiquitination: Mdm2 and beyond. Mol Cell 21:307–315

[9] Cervantes RB, Stringer JR, Shao C, Tischfield JA, Stambrook PJ (2002) Embryonic stem cells and somatic cells differ in mutation frequency and type. Proc Natl Acad Sci USA 99:3586–3590

[10] Chao C, Hergenhahn M, Kaeser MD, Wu Z, Saito S, Iggo R, Hollstein M, Appella E, Xu Y (2003) Cell type- and promoterspecific roles of Ser18 phosphorylation in regulating p53 responses. J Biol Chem 278:41028–41033

[11] Chao C, Herr D, Chun J, Xu Y (2006) Ser18 and 23 phosphorylation is required for p53-dependent apoptosis and tumor suppression. Embo J 25:2615–2622

[12] Chen Z, Zhao T, Xu Y (2012) The genomic stability of induced pluripotent stem cells. Protein Cell 3:271–277

[13] Cliff TS, Dalton S (2017) Metabolic switching and cell fate decisions: implications for pluripotency, reprogramming and development. Curr Opin Genet Dev 46:44–49

[14] Coutts M, Keirstead HS (2008) Stem cells for the treatment of spinal cord injury. Exp Neurol 209:368–377

[15] Craig AL, Burch L, Vojtesek B, Mikutowska J, Thompson A, Hupp TR (1999) Novel phosphorylation sites of human tumour suppressor protein p53 at Ser20 and Thr18 that disrupt the binding of mdm2 (mouse double minute 2) protein are modified in human cancers. Biochem J 342:133–141

[16] D’Amour KA, Bang AG, Eliazer S, Kelly OG, Agulnick AD, Smart NG,Moorman MA, Kroon E, Carpenter MK, Baetge EE (2006) Production of pancreatic hormone-expressing endocrine cells from human embryonic stem cells. Nat Biotech 24:1392–1401

[17] de Almeida PE, Meyer EH, Kooreman NG, Diecke S, Dey D, Sanchez-Freire V,Hu S, Ebert A, Odegaard J, Mordwinkin NM (2014) Transplanted terminally differentiated induced pluripotent stem cells are accepted by immune mechanisms similar to self-tolerance. Nat Commun 5:3903

[18] Deuse T,Hu X, Agbor-Enoh S, Koch M, Spitzer MH, Gravina A, Alawi M, Marishta A, Peters B,Kosaloglu-Yalcin Z, (2019) De novo mutations in mitochondrial DNA of iPSCs produce immunogenic neoepitopes in mice and humans. Nat Biotechnol 37:1137–1144

[19] Eischen CM (2016) Genome stability requires p53. Cold Spring Harb Perspect Med 6:a026096

[20] Fatica A, Bozzoni I (2014) Long non-coding RNAs: new players in cell differentiation and development. Nat Rev Genet 15:7–21

[21] Feng L, Lin T, Uranishi H, Gu W, Xu Y (2005) Functional analysis of the roles of posttranslational modifications at the p53 C terminus in regulating p53 stability and activity. Mol Cell Biol 25:5389–5395

[22] Feng L, Hollstein M, Xu Y (2006) Ser46 phosphorylation regulates p53-dependent apoptosis and replicative senescence. Cell Cycle 5:2812–2819 Epub 2006 Dec 2811

[23] Giorgetti A, Montserrat N, Aasen T, Gonzalez F, Rodràguez-Pizà I, Vassena R, Raya A, Boué S, Barrero MJ, Corbella BA (2009) Generation of induced pluripotent stem cells from human cord blood using OCT4 and SOX2. Cell Stem Cell 5:353–357

[24] Gore A, Li Z, Fung H-L, Young JE, Agarwal S, Antosiewicz-Bourget J, Canto I, Giorgetti A, Israel MA, Kiskinis E (2011) Somatic coding mutations in human induced pluripotent stem cells. Nature 471:63–67

[25] Gu W, Roeder RG (1997) Activation of p53 sequence-specific DNA binding by acetylation of the p53 C-terminal domain. Cell 90:595–606

[26] Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674

[27] He J,Rong Z, Fu X, Xu Y (2017) A safety checkpoint to eliminate cancer risk of the immune evasive cells derived from human embryonic stem cells. Stem Cells. https://doi.org/10.1002/stem. 2568

[28] Hollstein M, Sidransky D, Vogelstein B, Harris CC (1991) p53 mutations in human cancers. Science 253:49–53

[29] Hu W, Feng Z, Teresky AK, Levine AJ (2007) p53 regulates maternal reproduction through LIF. Nature 450:721–724

[30] Inoue K, Kurabayashi A, Shuin T, Ohtsuki Y,Furihata M (2012) Overexpression of p53 protein in human tumors. Med Mol Morphol 45:115–123

[31] Jain AK, Barton MC (2018) P53: emerging roles in stem cells, development and beyond. Development 145:dev158360

[32] Jain AK, Allton K, Iacovino M, Mahen E, Milczarek RJ, Zwaka TP, Kyba M, Barton MC (2012) p53 regulates cell cycle and microRNAs to promote differentiation of human embryonic stem cells. PLoS Biol 10:e1001268

[33] Jain AK, Xi Y, McCarthy R,Allton K, Akdemir KC, Patel LR, Aronow B, Lin C, Li W, Yang L (2016) LncPRESS1 Is a p53- regulated LncRNA that safeguards pluripotency by disrupting SIRT6-mediated de-acetylation of histone H3K56. Mol Cell 64:967–981

[34] Janic A, Valente LJ, Wakefield MJ, Di Stefano L, Milla L, Wilcox S, Yang H, Tai L, Vandenberg CJ, Kueh AJ (2018) DNA repair processes are critical mediators of p53-dependent tumor suppression. Nat Med 24:947–953

[35] Ji J, Ng SH, Sharma V, Neculai D, Hussein S, Sam M, Trinh Q, Church GM, McPherson JD, Nagy A (2012) Elevated coding mutation rate during the reprogramming of human somatic cells into induced pluripotent stem cells. Stem Cells 30:435–440

[36] Jiang J, Lv W, Ye X, Wang L, Zhang M, Yang H, Okuka M, Zhou C, Zhang X, Liu L (2013) Zscan4 promotes genomic stability during reprogramming and dramatically improves the quality of iPS cells as demonstrated by tetraploid complementation. Cell Res 23:92–106

[37] Kawamura T, Suzuki J, Wang YV, Menendez S, Morera LB, Raya A, Wahl GM, Belmonte JCI (2009) Linking the p53 tumour suppressor pathway to somatic cell reprogramming. Nature 460:1140–1144

[38] Kim JB, Zaehres H, Wu G, Gentile L, Ko K, Sebastiano V, Araúzo-Bravo MJ, Ruau D, Han DW, Zenke M (2008) Pluripotent stem cells induced from adult neural stem cells by reprogramming with two factors. Nature 454:646–650

[39] Kim JB, Sebastiano V, Wu G, Araúzo-Bravo MJ, Sasse P, Gentile L, Ko K, Ruau D, Ehrich M, van den Boom D (2009a) Oct4- induced pluripotency in adult neural stem cells. Cell 136:411–419

[40] Kim JV, Kang SS, Dustin ML, McGavern DB (2009b) Myelomonocytic cell recruitment causes fatal CNS vascular injury during acute viral meningitis. Nature 457:191–195

[41] Kim J, Yu L, Chen W, Xu Y, Wu M, Todorova D, Tang Q, Feng B, Jiang L, He J (2019) Wild-type p53 promotes cancer metabolic switch by inducing PUMA-dependent suppression of oxidative phosphorylation. Cancer Cell 35(2):191–203

[42] Kimbrel EA, Lanza R (2015) Current status of pluripotent stem cells: moving the first therapies to the clinic. Nat Rev Drug Discov 14:681–692

[43] Ko LJ, Prives C (1996) p53: puzzle and paradigm. Genes Dev 10:1054–1072

[44] Koifman G, Shetzer Y, Eizenberger S, Solomon H, Rotkopf R, Molchadsky A, Lonetto G, Goldfinger N, Rotter V (2018) A mutant p53-dependent embryonic stem cell gene signature is associated with augmented tumorigenesis of stem cells. Cancer Res 78:5833

[45] Kroon E, Martinson LA, Kadoya K, Bang AG, Kelly OG, Eliazer S, Young H, Richardson M, Smart NG, Cunningham J (2008) Pancreatic endoderm derived from human embryonic stem cells generates glucose-responsive insulin-secreting cells in vivo. Nat Biotech 26:443–452

[46] Labuschagne CF, Zani F, Vousden KH (2018) Control of metabolism by p53: cancer and beyond. Biochim Biophys Acta 1870:32–42

[47] Lake BB, Fink J, Klemetsaune L, Fu X, Jeffers JR, Zambetti GP, Xu Y (2012) Context-dependent enhancement of induced pluripotent stem cell reprogramming by silencing Puma. Stem cells 30:888–897

[48] Lane DP (1992) p53, guardian of the genome. Nature 358:15–16

[49] Lee D-F, Su J, Ang Y-S, Carvajal-Vergara X, Mulero-Navarro S, Pereira Carlos F, Gingold J, Wang H-L, Zhao R, Sevilla A (2012) Regulation of embryonic and induced pluripotency by aurora kinase-p53 signaling. Cell Stem Cell 11:179–194

[50] Levine AJ (1997) p53, the cellular gatekeeper for growth and division. Cell 88:323–331

[51] Li W, Wei W, Zhu S, Zhu J, Shi Y, Lin T, Hao E, Hayek A, Deng H, Ding S (2009) Generation of rat and human induced pluripotent stem cells by combining genetic reprogramming and chemical inhibitors. Cell Stem Cell 4:16–19

[52] Li M, He Y, Dubois W, Wu X, Shi J, Huang J (2012) Distinct regulatory mechanisms and functions for p53-activated and p53- repressed DNA damage response genes in embryonic stem cells. Mol Cell 46:30–42

[53] Li Z, Lu H, Yang W, Yong J, Zhang Z-N, Zhang K, Deng H, Xu Y (2014) Mouse SCNT ESCs have lower somatic mutation load than syngeneic iPSCs. Stem Cell Rep 2:399–405

[54] Li L, Mao Y, Zhao L, Li L, Wu J,Zhao M, Du W, Yu L, Jiang P (2019) p53 regulation of ammonia metabolism through urea cycle controls polyamine biosynthesis. Nature 567:253–256

[55] Lin T, Chao C, Saito SI, Mazur SJ, Murphy ME, Appella E, Xu Y (2005) p53 induces differentiation of mouse embryonic stem cells by suppressing Nanog expression. Nat Cell Biol 7:165–171

[56] Lin N, Chang K-Y, Li Z, Gates K, Rana Zacharia A, Dang J, Zhang D, Han T, Yang C-S, Cunningham Thomas J (2014) An evolutionarily conserved long noncoding RNA TUNA controls pluripotency and neural lineage commitment. Mol Cell 53:1005–1019

[57] Liu D, Xu Y (2010) p53, oxidative stress, and aging. Antioxid Redox Signal 15:1669–1678

[58] Mandai M, Watanabe A, Kurimoto Y,Hirami Y, Morinaga C, Daimon T, Fujihara M, Akimaru H, Sakai N, Shibata Y (2017) Autologous induced stem-cell-derived retinal cells for macular degeneration. N Engl J Med 376:1038–1046

[59] Marión RM, Strati K, Li H, Murga M, Blanco R, Ortega S, Fernandez-Capetillo O, Serrano M, Blasco MA (2009) A p53-mediated DNA damage response limits reprogramming to ensure iPS cell genomic integrity. Nature 460:1149–1153

[60] Matsa E, Ahrens JH, Wu JC (2016) Human induced pluripotent stem cells as a platform for personalized and precision cardiovascular medicine. Physiol Rev 96:1093–1126

[61] Menendez D, Inga A, Resnick MA (2009) The expanding universe of p53 targets. Nat Rev Cancer 9:724–737

[62] Merkle FT, Ghosh S, Kamitaki N, Mitchell J, Avior Y, Mello C, Kashin S, Mekhoubad S, Ilic D, Charlton M (2017) Human pluripotent stem cells recurrently acquire and expand dominant negative P53 mutations. Nature 545:229–233

[63] Muller PAJ, Vousden KH (2013) p53 mutations in cancer. Nature Cell Biology 15:2–8

[64] Mummery C (2011) Induced pluripotent stem cells—a cautionary note. N Engl J Med 364:2160–2162

[65] Murphy M, Ahn J, Walker KK, Hoffman WH, Evans RM, Levine AJ, George DL (1999) Transcriptional repression by wild-type p53 utilizes histone deacetylases, mediated by interaction with mSin3a. Genes Dev 13:2490–2501

[66] Oliner JD, Saiki AY, Caenepeel S (2016) The role of MDM2 amplification and overexpression in tumorigenesis. Cold Spring Harb Perspect Med 6:a026336

[67] Park IH, Zhao R, West JA, Yabuuchi A, Huo H, Ince TA, Lerou PH, Lensch MW, Daley GQ (2008) Reprogramming of human somatic cells to pluripotency with defined factors. Nature 451:141–146

[68] Passier R, van Laake LW, Mummery CL (2008) Stem-cell-based therapy and lessons from the heart. Nature 453:322–329

[69] Rinn JL (2014) lncRNAs: linking RNA to chromatin. Cold Spring Harb Perspect Biol 6:a018614–a018614

[70] Robertson NJ, Brook FA, Gardner RL, Cobbold SP, Waldmann H, Fairchild PJ (2007) Embryonic stem cell-derived tissues are immunogenic but their inherent immune privilege promotes the induction of tolerance. Proc Natl Acad Sci USA 104:20920–20925

[71] Rong Z, Wang M, Hu Z, Stradner M, Zhu S, Kong H, Yi H, Goldrath A, Yang Y-G, Xu Y (2014) An effective approach to prevent immune rejection of human ESC-derived allografts. Cell Stem Cell 14:121–130

[72] Sabapathy K, Lane DP (2017) Therapeutic targeting of p53: all mutants are equal, but some mutants are more equal than others. Nat Rev Clin Oncol 15:13

[73] Saito S, Goodarzi AA, Hagashimoto Y, Noda Y,Lees-Miller SP, Appella E, Anderson CW (2002) ATM mediates phosphorylation at multiple p53 sites, including Ser46, in response to ionizing radiation. J Biol Chem 277(15):12491–12494

[74] Shi Y, Desponts C, Do JT, Hahm HS, Schˆler HR, Ding S(2008) Induction of pluripotent stem cells from mouse embryonic fibroblasts by Oct4 and Klf4 with small-molecule compounds. Cell Stem Cell 3:568–574

[75] Shieh SY, Taya Y, Prives C (1999) DNA damage-inducible phosphorylation of p53 at N-terminal sites including a novel site, Ser20, requires tetramerization. Embo J 18:1815–1823

[76] Smith ZD, Nachman I,Regev A, Meissner A (2010) Dynamic singlecell imaging of direct reprogramming reveals an early specifying event. Nat Biotechnol 28:521–526

[77] Soldner F, Jaenisch R (2012) iPSC disease modeling. Science 338:1155–1156

[78] Son MJ, Son MY, Seol B, Kim MJ, Yoo CH, Han MK, Cho YS (2013) Nicotinamide overcomes pluripotency deficits and reprogramming barriers. Stem Cells 31:1121–1135

[79] Song J, Chao C, Xu Y (2007) Ser18 and Ser23 phosphorylation plays synergistic roles in activating p53-dependent neuronal apoptosis. Cell Cycle 6:1411–1413

[80] Song H, Chung S-K, Xu Y (2010) Modeling disease in human ESCs using an efficient BAC-based homologous recombination system. Cell Stem Cell 6:80–89

[81] Soussi T, Béroud C (2001) Assessing TP53 status in human tumours to evaluate clinical outcome. Nat Rev Cancer 1:233–239

[82] Tachibana M, Amato P, Sparman M, Gutierrez Nuria M, Tippner-Hedges R, Ma H, Kang E,Fulati A, Lee H-S, Sritanaudomchai H (2013) Human embryonic stem cells derived by somatic cell nuclear transfer. Cell 153:1228–1238

[83] Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126:663–676

[84] Tang Y, Luo J, Zhang W, Gu W (2006) Tip60-dependent acetylation of p53 modulates the decision between cell-cycle arrest and apoptosis. Mol Cell 24:827–839

[85] Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS, Jones JM (1998) Embryonic stem cell lines derived from human blastocysts. Science 282:1145–1147

[86] Todorova D, Kim J, Hamzeinejad S, He J,Xu Y (2016) Brief report: immune microenvironment determines the immunogenicity of induced pluripotent stem cell derivatives. Stem Cells 34:510–515

[87] Trigiante G, Lu X (2006) ASPP [corrected] and cancer. Nat Rev Cancer 6:217–226

[88] Trounson A (2009) Rats, cats, and elephants, but still no unicorn: induced pluripotent stem cells from new species. Cell Stem Cell 4:3–4

[89] Unger T, Juven-Gershon T, Moallem E, Berger M, Vogt Sionov R, Lozano G, Oren M, Haupt Y (1999) Critical role for Ser20 of human p53 in the negative regulation of p53 by Mdm2. Embo J 18:1805–1814

[90] Utikal J,Polo JM, Stadtfeld M, Maherali N, Kulalert W, Walsh RM, Khalil A, Rheinwald JG, Hochedlinger K (2009) Immortalization eliminates a roadblock during cellular reprogramming into iPS cells. Nature 460:1145–1148

[91] Vousden KH, Prives C (2009) Blinded by the light: the growing complexity of p53. Cell 137:413–431

[92] Weisz L, Oren M, Rotter V (2007) Transcription regulation by mutant p53. Oncogene 26:2202–2211

[93] Wu Z, Earle J, Saito S, Anderson CW, Appella E, Xu Y (2002) Mutation of mouse p53 Ser23 and the response to DNA damage. Mol Cell Biol 22:2441–2449

[94] Xu Y (2005) A new role of p53 in maintaining genetic stability in embryonic stem cells. Cell Cycle 4:363–364

[95] Xu H, Wang B, Ono M, Kagita A, Fujii K,Sasakawa N, Ueda T, Gee P, Nishikawa M, Nomura M (2019) Targeted disruption of HLA genes via CRISPR-Cas9 generates iPSCs with enhanced immune compatibility. Cell Stem Cell 24:566–578.e567

[96] Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, Nie J, Jonsdottir GA, Ruotti V, Stewart R (2007) Induced pluripotent stem cell lines derived from human somatic cells. Science 318:1917–1920

[97] Zhang Z-N, Chung S-K, Xu Z, Xu Y (2014) Oct4 maintains the pluripotency of human embryonic stem cells by inactivating p53 through Sirt1-mediated deacetylation. Stem Cells 32:157–165

[98] Zhao T, Xu Y (2010) P53 and stem cells: new developments and new concerns. Trends Cell Biol 20:170–175

[99] Zhao Y, Yin X, Qin H, Zhu F, Liu H, Yang W, Zhang Q, Xiang C, Hou P, Song Z (2008) Two supporting factors greatly improve the efficiency of human iPSC generation. Cell Stem Cell 3:475–479

[100] Zhao XY, Li W, Lv Z, Liu L, Tong M, Hai T, Hao J, Guo CL, Ma QW, Wang L (2009) iPS cells produce viable mice through tetraploid complementation. Nature 461:86–90

[101] Zhao T, Zhang Z-N, Rong Z, Xu Y (2011) Immunogenicity of induced pluripotent stem cells. Nature 474:212–215

[102] Zhao T, Zhang Z-N, Westenskow PD, Todorova D, Hu Z, Lin T, Rong Z, Kim J, He J, Wang M (2015) Humanized mice reveal differential immunogenicity of cells derived from autologous induced pluripotent stem cells. Cell Stem Cell 17:353–359

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