Skip to main content
SpringerLink
Log in
Book cover

p53 in the Clinics pp 65–76Cite as

The p53 Family and Stem Cell Biology

  • Chapter
  • First Online:

  • 1026 Accesses

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.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  • 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 403:13–17

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Ambros V (2004) The functions of animal microRNAs. Nature 431:350–355

    Article  PubMed  CAS  Google Scholar 

  • 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 158:1378–1389

    Article  PubMed  CAS  Google Scholar 

  • 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):126–140

    Article  PubMed  CAS  Google Scholar 

  • Bagchi A, Mills AA (2008) The quest for the 1p36 tumor suppressor. Cancer Res 68:2551–2556

    Article  PubMed  CAS  Google Scholar 

  • Barrandon Y, Green H (1985) Cell size as a determinant of the clone-forming ability of human keratinocytes. Proc Natl Acad Sci USA 82:5390–5394

    Article  PubMed  CAS  Google Scholar 

  • Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 16:281–297

    Article  Google Scholar 

  • 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):251–263

    Article  PubMed  CAS  Google Scholar 

  • 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):315–326

    Article  PubMed  CAS  Google Scholar 

  • Billon N, Terrinoni A, Jolicoeur C, McCarthy A, Richardson WD, Melino G, Raff M (2004) Roles for p53 and p73 during oligodendrocyte development. Development 131:1211–1220

    Article  PubMed  CAS  Google Scholar 

  • 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 122:947–956

    Article  PubMed  CAS  Google Scholar 

  • 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 146:3062–3069

    Google Scholar 

  • 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 13:1037–1047

    Article  PubMed  CAS  Google Scholar 

  • 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 104:11999–12004

    Article  PubMed  CAS  Google Scholar 

  • 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):643–655

    Article  PubMed  CAS  Google Scholar 

  • 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 448:313–317

    Article  Google Scholar 

  • 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]

    Article  PubMed  Google Scholar 

  • Daley GQ (2010) Stem cells: roadmap to the clinic. J Clin Invest 120:8–10

    Article  PubMed  CAS  Google Scholar 

  • Dötsch V, Bernassola F, Coutandin D, Candi E, Melino G (2010) p63 and p73 the ancestors of p53. Cold Spring Harb Perspect Biol 2:1–14

    Article  Google Scholar 

  • 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 20:2058–2065

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • Graham V, Khudyakov J, Ellis P, Pevny L (2003) SOX2 functions to maintain neural progenitor identity. Neuron 39(5):749–765

    Article  PubMed  CAS  Google Scholar 

  • 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):93–104

    Article  PubMed  CAS  Google Scholar 

  • Haojian Zhang, Wang ZZ (2008) Mechanisms that mediate stem cell self-renewal and differentiation. J Cell Biochem 103:709–718

    Article  Google Scholar 

  • 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):846–858

    Article  PubMed  CAS  Google Scholar 

  • 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 460:1132–1135

    Article  PubMed  CAS  Google Scholar 

  • Ivanova NB, Dimos JT, Schaniel C, Hackney JA, Moore KA, Lemischka IR (2002) A stem cell molecular signature. Science 298:601–604

    Article  PubMed  CAS  Google Scholar 

  • 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 90:809–819

    Article  PubMed  CAS  Google Scholar 

  • 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 460:1140–1144

    Article  PubMed  CAS  Google Scholar 

  • 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 15:1187–1195

    Article  PubMed  CAS  Google Scholar 

  • 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 7:165–171

    Article  PubMed  CAS  Google Scholar 

  • 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 38:431–440

    Article  PubMed  CAS  Google Scholar 

  • 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):189

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • Meletis K, Wirta V, Hede SM, Nistér M, Lundeberg J, Frisén J (2006) p53 suppresses the self-renewal of adult neural stem cells. Development 133:363–369

    Article  PubMed  CAS  Google Scholar 

  • Melino G, De Laurenzi V, Vousden KH (2002) p73: friend or foe in tumorigenesis. Nat Rev Cancer 8:605–615

    Article  Google Scholar 

  • 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 398:708–713

    Article  PubMed  CAS  Google Scholar 

  • 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):631–642

    Article  PubMed  CAS  Google Scholar 

  • Molofsky AV, Pardal R, Morrison SJ (2004) Diverse mechanisms regulate stem cell self-renewal. Curr Opin Cell Biol 16:700–707

    Article  PubMed  CAS  Google Scholar 

  • 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):379–391

    Article  PubMed  CAS  Google Scholar 

  • 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):2048–2060

    Article  PubMed  CAS  Google Scholar 

  • 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):372–376

    Article  PubMed  CAS  Google Scholar 

  • Okita K, Ichisaka T, Yamanaka S (2007) Generation of germline-competent induced pluripotent stem cells. Nature 448:313–317

    Article  PubMed  CAS  Google Scholar 

  • Pelengaris S, Khan M, Evan G (2002) c-MYC: more than just a matter of life and death. Nat Rev Cancer 2:764–776

    Article  PubMed  CAS  Google Scholar 

  • 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 98:3156–3161

    Article  PubMed  CAS  Google Scholar 

  • 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):409–414

    Article  PubMed  CAS  Google Scholar 

  • Senoo M, Pinto F, Crum CP, McKeon F (2007) p63 is essential for the proliferative potential of stem cells in stratified epithelia. Cell 129:523–536

    Article  PubMed  CAS  Google Scholar 

  • Shenghui H, Nakada D, Morrison SJ (2009) Mechanisms of stem cell self-renewal. Annu Rev Cell Dev Biol 25:377–406

    Article  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • 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 5:64–75

    Article  PubMed  CAS  Google Scholar 

  • 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 444:624–628

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • 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 17:1816–1829

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Vousden KH, Lane DP (2007) p53 in health and disease. Nat Rev Mol Cell Biol 8:275–283

    Article  PubMed  CAS  Google Scholar 

  • 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 398:714–718

    Article  PubMed  CAS  Google Scholar 

  • 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 404:99–103

    Article  PubMed  CAS  Google Scholar 

  • Yang A, Kaghad M, Caput D, McKeon F (2002) On the shoulder of giants: p63, p73 and the rise of p53. Trends Genet 2:90–95

    Article  Google Scholar 

  • Yi R, Poy MN, Stoffel M, Fuchs E (2008) A skin microRNA promotes differentiation by repressing ‘stemness’. Nature 452:225–229

    Article  PubMed  CAS  Google Scholar 

  • 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):281–292

    Article  PubMed  CAS  Google Scholar 

  • 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):183–186

    Article  PubMed  CAS  Google Scholar 

  • 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 3:475–479

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

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

Author information

Authors and Affiliations

  1. Medical Research Council, Toxicology Unit, Leicester University, Leicester, LE1 9HN, UK

    Massimiliano Agostini, Alessandro Rufini, Edward T. W. Bampton, Gerry Melino & Richard A. Knight

  2. Biochemistry IDI-IRCCS Laboratory, Department of Experimental Medicine, University of Rome Tor Vergata, 00133, Rome, Italy

    Francesca Bernassola & Gerry Melino

Authors
  1. Massimiliano Agostini
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alessandro Rufini
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Edward T. W. Bampton
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Francesca Bernassola
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Gerry Melino
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Richard A. Knight
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Massimiliano Agostini or Alessandro Rufini .

Editor information

Editors and Affiliations

  1. International Prevention Research Instit, 95 cours Lafayette, Lyon, 69006, France

    Pierre Hainaut

  2. International Agency for Cancer Research, 150 Cours Albert-Thomas, Lyon, 69372, France

    Magali Olivier

  3. Cancer Center Karolinska (CCK), Dept. Oncology and Pathology, Karolinska Institute, Karolinska Institutet, Stockholm, 171 76, Sweden

    Klas G. Wiman

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer Science+Business Media New York

About this chapter

Cite this chapter

Agostini, M., Rufini, A., Bampton, E.T.W., Bernassola, F., Melino, G., Knight, R.A. (2013). The p53 Family and Stem Cell Biology. In: Hainaut, P., Olivier, M., Wiman, K. (eds) p53 in the Clinics. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-3676-8_4

Download citation

Publish with us

Policies and ethics

Search

Navigation