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The p53 Family and Stem Cell Biology

  • Massimiliano Agostini
  • Alessandro Rufini
  • Edward T. W. Bampton
  • Francesca Bernassola
  • Gerry Melino
  • Richard A. Knight
Chapter

Abstract

Stem cells are characterized by the ability to renew themselves (self-renewal) and the capability to generate all the cells within the human body. These features are achieved by a fine-tuned control of proliferation and maintenance of the undifferentiated condition. Transcription factors such as Nanog, Sox, and Oct-4 and extrinsic factors (LIF, BMP, and FGF) have been demonstrated to play a critical role in the regulation of stemness. Because stem cells are under consideration in clinics for cell-based therapy, it is important to understand the molecular mechanisms underlying stemness. In this chapter, we revisit stem cell biology and add a new layer of complexity. In particular, we will discuss the role of the p53 family (p53, p63, and p73) in the regulation of self-renewal, proliferation, and differentiation of stem cells.

Keywords

Stem Cell Leukemia Inhibitor Factor Adult Stem Cell Stem Cell Biology Stem Cell Compartment 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

This work was supported by the Medical Research Council, and by grants from AIRC, Telethon, and Min Sanita’ to G.M.

References

  1. Agostini M, Tucci P, Chen H, Knight RA, Bano D, McKeon F, Nicotera P, Melino G (2010) p73 regulates maintenance of neural stem cell. Biochem Biophys Res Commun 403:13–17PubMedCrossRefGoogle Scholar
  2. 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 8:145–155PubMedCrossRefGoogle Scholar
  3. Ambros V (2004) The functions of animal microRNAs. Nature 431:350–355PubMedCrossRefGoogle Scholar
  4. Armesilla-Diaz A, Bragado P, Del Valle I, Cuevas E, Lazaro I, Martin C, Cigudosa JC, Silva A (2009) p53 regulates the self-renewal and differentiation of neural precursors. Neuroscience 158:1378–1389PubMedCrossRefGoogle Scholar
  5. Avilion AA, Nicolis SK, Pevny LH, Perez L, Vivian N, Lovell-Badge R (2003) Multipotent cell lineages in early mouse development depend on SOX2 function. Genes Dev 17(1):126–140PubMedCrossRefGoogle Scholar
  6. Bagchi A, Mills AA (2008) The quest for the 1p36 tumor suppressor. Cancer Res 68:2551–2556PubMedCrossRefGoogle Scholar
  7. Barrandon Y, Green H (1985) Cell size as a determinant of the clone-forming ability of human keratinocytes. Proc Natl Acad Sci USA 82:5390–5394PubMedCrossRefGoogle Scholar
  8. Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 16:281–297CrossRefGoogle Scholar
  9. Batlle E, Henderson JT, Beghtel H, van den Born MM, Sancho E, Huls G, Meeldijk J, Robertson J, van de Wetering M, Pawson T, Clevers H (2002) Beta-catenin and TCF mediate cell positioning in the intestinal epithelium by controlling the expression of EphB/ephrinB. Cell 111(2):251–263PubMedCrossRefGoogle Scholar
  10. Bernstein BE, Mikkelsen TS, Xie X, Kamal M, Huebert DJ, Cuff J, Fry B, Meissner A, Wernig M, Plath K, Jaenisch R, Wagschal A, Feil R, Schreiber SL, Lander ES (2006) A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 125(2):315–326PubMedCrossRefGoogle Scholar
  11. Billon N, Terrinoni A, Jolicoeur C, McCarthy A, Richardson WD, Melino G, Raff M (2004) Roles for p53 and p73 during oligodendrocyte development. Development 131:1211–1220PubMedCrossRefGoogle Scholar
  12. Boyer LA, Lee TI, Cole MF, Johnstone SE, Levine SS, Zucker JP, Guenther MG, Kumar RM, Murray HL, Jenner RG, Gifford DK, Melton DA, Jaenisch R, Young RA (2005) Core transcriptional regulatory circuitry in human embryonic stem cells. Cell 122:947–956PubMedCrossRefGoogle Scholar
  13. Campeau PM, Ah Mew N, Cartier L, Mackay KL, Shaffer LG, Der Kaloustian VM, Thomas MA (2008) Prenatal diagnosis of monosomy 1p36: a focus on brain abnormalities and a review of the literature. Am J Med Genet A 146:3062–3069Google Scholar
  14. Candi E, Rufini A, Terrinoni A, Dinsdale D, Ranalli M, Paradisi A, De Laurenzi V, Spagnoli LG, Catani MV, Ramadan S, Knight RA, Melino G (2006) Differential roles of p63 isoforms in epidermal development: selective genetic complementation in p63 null mice. Cell Death Differ 13:1037–1047PubMedCrossRefGoogle Scholar
  15. Candi E, Rufini A, Terrinoni A, Giamboi-Miraglia A, Lena AM, Mantovani R, Knight R, Melino G (2007) DNp63 regulates thymic development through enhanced expression of FgfR2 and Jag2. Proc Natl Acad Sci USA 104:11999–12004PubMedCrossRefGoogle Scholar
  16. Chambers I, Colby D, Robertson M, Nichols J, Lee S, Tweedie S, Smith A (2003) Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells. Cell 113(5):643–655PubMedCrossRefGoogle Scholar
  17. Chin MH, Mason MJ, Xie W, Volinia S, Singer M, Peterson C, Ambartsumyan G, Okita K, Ichisaka T, Yamanaka S (2007) Generation of germline-competent induced pluripotent stem cells. Nature 448:313–317CrossRefGoogle Scholar
  18. Dahéron L, Opitz SL, Zaehres H, Lensch MW, Andrews PW, Itskovitz-Eldor J, Daley GQ (2004) LIF/STAT3 signaling fails to maintain self-renewal of human embryonic stem cells. Stem Cells 22(5):770–778, Erratum in: Stem Cells. 2007 Dec;25(12):3273. Lensch, William M [corrected to Lensch, M William]PubMedCrossRefGoogle Scholar
  19. Daley GQ (2010) Stem cells: roadmap to the clinic. J Clin Invest 120:8–10PubMedCrossRefGoogle Scholar
  20. Dötsch V, Bernassola F, Coutandin D, Candi E, Melino G (2010) p63 and p73 the ancestors of p53. Cold Spring Harb Perspect Biol 2:1–14CrossRefGoogle Scholar
  21. Fujitani M, Cancino GI, Dugani CB, Weaver IC, Gauthier-Fisher A, Paquin A, Mak TW, Wojtowicz MJ, Miller FD, Kaplan DR (2010) TAp73 acts via the bHLH Hey2 to promote long-term maintenance of neural precursors. Curr Biol 20:2058–2065PubMedCrossRefGoogle Scholar
  22. González-Cano L, Herreros-Villanueva M, Fernández-Alonso R, Ayuso-Sacido Á, Meyer G, García-Verdugo JM, Silva A, Marqués MM, Marín MC (2010) p73 deficiency results in impaired self renewal and premature neuronal differentiation of mouse neural progenitors independently of p53. Cell Death Dis 1:e109. doi: 10.1038/cddis.2010.87 PubMedCrossRefGoogle Scholar
  23. Graham V, Khudyakov J, Ellis P, Pevny L (2003) SOX2 functions to maintain neural progenitor identity. Neuron 39(5):749–765PubMedCrossRefGoogle Scholar
  24. Hansen D, Wilson-Berry L, Dang T, Schedl T (2004) Control of the proliferation versus meiotic development decision in the C. elegans germline through regulation of GLD-1 protein accumulation. Development 131(1):93–104PubMedCrossRefGoogle Scholar
  25. Haojian Zhang, Wang ZZ (2008) Mechanisms that mediate stem cell self-renewal and differentiation. J Cell Biochem 103:709–718CrossRefGoogle Scholar
  26. Hitoshi S, Alexson T, Tropepe V, Donoviel D, Elia AJ, Nye JS, Conlon RA, Mak TW, Bernstein A, van der Kooy D (2002) Notch pathway molecules are essential for the maintenance, but not the generation, of mammalian neural stem cells. Genes Dev 16(7):846–858PubMedCrossRefGoogle Scholar
  27. Hong H, Takahashi K, Ichisaka T, Aoi T, Kanagawa O, Nakagawa M, Okita K, Yamanaka S (2009) Suppression of induced pluripotent stem cell generation by the p53-p21 pathway. Nature 460:1132–1135PubMedCrossRefGoogle Scholar
  28. Ivanova NB, Dimos JT, Schaniel C, Hackney JA, Moore KA, Lemischka IR (2002) A stem cell molecular signature. Science 298:601–604PubMedCrossRefGoogle Scholar
  29. Kaghad M, Bonnet H, Yang A, Creancier L, Biscan JC, Valent A, Minty A, Chalon P, Lelias JM, Dumont X, Ferrara P, McKeon F, Caput D (1997) Monoallelically expressed gene related to p53 at 1p36, a region frequently deleted in neuroblastoma and other human cancers. Cell 90:809–819PubMedCrossRefGoogle Scholar
  30. Kawamura T, Suzuki J, Wang YV, Menendez S, Morera LB, Raya A, Wahl GM, Belmonte JC (2009) Linking the p53 tumour suppressor pathway to somatic cell reprogramming. Nature 460:1140–1144PubMedCrossRefGoogle Scholar
  31. Lena AM, Shalom-Feuerstein R, di Val R, Cervo P, Aberdam D, Knight RA, Melino G, Candi E (2008) miR-203 represses ‘stemness’ by repressing DNp63. Cell Death Differ 15:1187–1195PubMedCrossRefGoogle Scholar
  32. Lin T, Chao C, Saito S, Mazur SJ, Murphy ME, Appella E, Xu Y (2005) p53 induces differentiation of mouse embryonic stem cells by suppressing Nanog expression. Nat Cell Biol 7:165–171PubMedCrossRefGoogle Scholar
  33. Loh YH, Wu Q, Chew JL, Vega VB, Zhang W, Chen X, Bourque G, George J, Leong B, Liu J, Wong KY, Sung KW, Lee CW, Zhao XD, Chiu KP, Lipovich L, Kuznetsov VA, Robson P, Stanton LW, Wei CL, Ruan Y, Lim B, Ng HH (2006) The Oct4 and Nanog transcription ­network regulates pluripotency in mouse embryonic stem cells. Nat Genet 38:431–440PubMedCrossRefGoogle Scholar
  34. Machold R, Hayashi S, Rutlin M, Muzumdar MD, Nery S, Corbin JG, Gritli-Linde A, Dellovade T, Porter JA, Rubin LL, Dudek H, McMahon AP, Fishell G (2003) Sonic hedgehog is required for progenitor cell maintenance in telencephalic stem cell niches. Neuron 39(6):937–950, Erratum in: Neuron. 2003 Sep 25;40(1):189PubMedCrossRefGoogle Scholar
  35. 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 460:1149–1153PubMedCrossRefGoogle Scholar
  36. Meletis K, Wirta V, Hede SM, Nistér M, Lundeberg J, Frisén J (2006) p53 suppresses the self-renewal of adult neural stem cells. Development 133:363–369PubMedCrossRefGoogle Scholar
  37. Melino G, De Laurenzi V, Vousden KH (2002) p73: friend or foe in tumorigenesis. Nat Rev Cancer 8:605–615CrossRefGoogle Scholar
  38. Mills AA, Zheng B, Wang XJ, Vogel H, Roop DR, Bradley A (1999) p63 is a p53 homologue required for limb and epidermal morphogenesis. Nature 398:708–713PubMedCrossRefGoogle Scholar
  39. Mitsui K, Tokuzawa Y, Itoh H, Segawa K, Murakami M, Takahashi K, Maruyama M, Maeda M, Yamanaka S (2003) The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cells. Cell 113(5):631–642PubMedCrossRefGoogle Scholar
  40. Molofsky AV, Pardal R, Morrison SJ (2004) Diverse mechanisms regulate stem cell self-renewal. Curr Opin Cell Biol 16:700–707PubMedCrossRefGoogle Scholar
  41. Nichols J, Zevnik B, Anastassiadis K, Niwa H, Klewe-Nebenius D, Chambers I, Schöler H, Smith A (1998) Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4. Cell 95(3):379–391PubMedCrossRefGoogle Scholar
  42. Niwa H, Burdon T, Chambers I, Smith A (1998) Self-renewal of pluripotent embryonic stem cells is mediated via activation of STAT3. Genes Dev 12(13):2048–2060PubMedCrossRefGoogle Scholar
  43. Niwa H, Miyazaki J, Smith AG (2000) Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells. Nat Genet 24(4):372–376PubMedCrossRefGoogle Scholar
  44. Okita K, Ichisaka T, Yamanaka S (2007) Generation of germline-competent induced pluripotent stem cells. Nature 448:313–317PubMedCrossRefGoogle Scholar
  45. Pelengaris S, Khan M, Evan G (2002) c-MYC: more than just a matter of life and death. Nat Rev Cancer 2:764–776PubMedCrossRefGoogle Scholar
  46. Pellegrini G, Dellambra E, Golisano O, Martinelli E, Fantozzi I, Bondanza S, Ponzin D, McKeon F, De Luca M (2001) p63 identifies keratinocyte stem cells. Proc Natl Acad Sci USA 98:3156–3161PubMedCrossRefGoogle Scholar
  47. Reya T, Duncan AW, Ailles L, Domen J, Scherer DC, Willert K, Hintz L, Nusse R, Weissman IL (2003) A role for Wnt signalling in self-renewal of haematopoietic stem cells. Nature 423(6938):409–414PubMedCrossRefGoogle Scholar
  48. Senoo M, Pinto F, Crum CP, McKeon F (2007) p63 is essential for the proliferative potential of stem cells in stratified epithelia. Cell 129:523–536PubMedCrossRefGoogle Scholar
  49. Shenghui H, Nakada D, Morrison SJ (2009) Mechanisms of stem cell self-renewal. Annu Rev Cell Dev Biol 25:377–406CrossRefGoogle Scholar
  50. Song H, Chung SK, Xu Y (2010) Modeling disease in human ESCs using an efficient BAC-based homologous recombination system. Cell Stem Cell 6:80–89PubMedCrossRefGoogle Scholar
  51. Su X, Paris M, Gi YJ, Tsai KY, Cho MS, Lin YL, Biernaskie JA, Sinha S, Prives C, Pevny LH, Miller FD, Flores ER (2009) TAp63 prevents premature aging by promoting adult stem cell maintenance. Cell Stem Cell 5:64–75PubMedCrossRefGoogle Scholar
  52. Suh EK, Yang A, Kettenbach A, Bamberger C, Michaelis AH, Zhu Z, Elvin JA, Bronson RT, Crum CP, McKeon F (2006) p63 protects the female germ line during meiotic arrest. Nature 444:624–628PubMedCrossRefGoogle Scholar
  53. Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126:663–676PubMedCrossRefGoogle Scholar
  54. Talos F, Abraham A, Holembowski L, Vaseva A, Tsirka S, Scheel A, Bode D, Dobbelstein M, Bruck W, Moll UM (2010) p73 is an essential regulator of neural stem cell maintenance in embryonal and adult CNS neurogenesis. Cell Death Differ 17:1816–1829PubMedCrossRefGoogle Scholar
  55. 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 460:1145–1148PubMedCrossRefGoogle Scholar
  56. Vousden KH, Lane DP (2007) p53 in health and disease. Nat Rev Mol Cell Biol 8:275–283PubMedCrossRefGoogle Scholar
  57. Yang A, Schweitzer R, Sun D, Kaghad M, Walker N, Bronson RT, Tabin C, Sharpe A, Caput D, Crum C, McKeon F (1999) p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development. Nature 398:714–718PubMedCrossRefGoogle Scholar
  58. Yang A, Walker N, Bronson R, Kaghad M, Oosterwegel M, Bonnin J, Vagner C, Bonnet H, Dikkes P, Sharpe A, McKeon F, Caput D (2000) p73-deficient mice have neurological, pheromonal and inflammatory defects but lack spontaneous tumors. Nature 404:99–103PubMedCrossRefGoogle Scholar
  59. Yang A, Kaghad M, Caput D, McKeon F (2002) On the shoulder of giants: p63, p73 and the rise of p53. Trends Genet 2:90–95CrossRefGoogle Scholar
  60. Yi R, Poy MN, Stoffel M, Fuchs E (2008) A skin microRNA promotes differentiation by repressing ‘stemness’. Nature 452:225–229PubMedCrossRefGoogle Scholar
  61. Ying QL, Nichols J, Chambers I, Smith A (2003a) BMP induction of Id proteins suppresses differentiation and sustains embryonic stem cell self-renewal in collaboration with STAT3. Cell 115(3):281–292PubMedCrossRefGoogle Scholar
  62. Ying QL, Stavridis M, Griffiths D, Li M, Smith A (2003b) Conversion of embryonic stem cells into neuroectodermal precursors in adherent monoculture. Nat Biotechnol 21(2):183–186PubMedCrossRefGoogle Scholar
  63. Zhao Y, Yin X, Qin H, Zhu F, Liu H, Yang W, Zhang Q, Xiang C, Hou P, Song Z, Liu Y, Yong J, Zhang P, Cai J, Liu M, Li H, Li Y, Qu X, Cui K, Zhang W, Xiang T, Wu Y, Zhao Y, Liu C, Yu C, Yuan K, Lou J, Ding M, Deng H (2008) Two supporting factors greatly improve the efficiency of human iPSC generation. Cell Stem Cell 3:475–479PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Massimiliano Agostini
    • 1
  • Alessandro Rufini
    • 1
  • Edward T. W. Bampton
    • 1
  • Francesca Bernassola
    • 2
  • Gerry Melino
    • 1
    • 2
  • Richard A. Knight
    • 1
  1. 1.Medical Research Council, Toxicology UnitLeicester UniversityLeicesterUK
  2. 2.Biochemistry IDI-IRCCS Laboratory, Department of Experimental MedicineUniversity of Rome Tor VergataRomeItaly

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