P53 and Cell Death

Abstract

The p53 transcription factor emerges not only as the most important tumour suppressor, but also as an intriguing scientific puzzle characterized by immense functional complexity. P53‐mediated apoptosis is a well‐established tumour suppression mechanism forming a critical barrier to tumourigenesis. Intense research into the mechanism of p53‐induced apoptosis revealed an involvement of p53 in the extrinsic and intrinsic cell death pathways, reactive oxygen species signalling and antisurvival responses. Notably, p53 exerts its effects by various direct and indirect mechanisms engaging transcriptional activation or repression of target genes as well as transcriptional independent modes of action. Importantly, more than 20 years of intense research has paved the way for a rational design of selective anticancer therapies aimed at restoration of p53 functionality in cancer cells.

Key concepts:

  • Apoptosis (programmed cell death) is a fundamental cellular process during development, maintenance of tissue homeostasis, and in cellular response to stress.

  • P53 function is compromised in most cancer cases either by direct mutations (50%) or by indirect mechanisms

  • P53 is a transcriptional factor that binds to specific target DNA sequences to either transcriptionally activate or repress genes.

  • P53 activates multiple apoptotic signalling pathways (extrinsic and intrinsic) thereby promoting an efficient apoptotic response.

  • The majority of pro‐apoptotic activities of p53 are mediated through the induction of specific apoptotic target genes, e.g. Bax, Puma and Noxa.

  • P53 also contributes in the mitochondrial outer membrane permeabilization due to its relocalization to mitochondra and interaction with Bcl‐2‐family members.

  • Harnessing p53 for cancer therapy is a promising strategy to combat cancer by reactivating pro‐apoptotic function in neoplastic cells.

Keywords: apoptosis; mutant p53; gain of function; transcriptional activity; cancer therapy

Figure 1.

Multiple signals activate p53 to induce various growth inhibitory responses. P53 tumour suppressor protein responds to diverse intarcellular (e.g. oncogene activation) and extracellular stimuli (e.g. nutrients deprivation) through activation of relevant downstream mechanisms (e.g. apoptosis) that act to protect cells from oncogenic transformation.

Figure 2.

Regulation of p53 by Mdm2. The amount of p53 protein is determined mainly by the rate of ubiquitin‐mediated proteolysis. Mdm2 is the E3 ligase of p53, inhibiting its activity and promoting it for degradation. In response to stress, the negative loop between p53 and Mdm2 is interrupted by proteins such as ARF, and by posttranslational modifications of p53 and Mdm2. ARF can be induced by oncogenes such as Myc or E1A resulting in p53 accumulation and apoptosis. Also, various posttranslational modifications of p53 and Mdm2 prevent Mdm2‐mediated degradation of p53.

Figure 3.

P53 activates the extrinsic and intrinsic cell death pathways. P53 activates the extrinsic pathway by directly inducing the expression of death receptors, such as Fas/CD95 or DR‐5 as well as caspases 8 and 6. P53 also activates the intrinsic pathway where p53 act at multiple levels mainly through transactivation of multiple genes associated with the mitochondria as well as downstream factors such as: Apaf‐1. Small yellow circles mark p53 target genes, whereas an orange small circle indicates p53‐repressed gene.

Figure 4.

Structure of p53 family members and their roles in growth suppression and development. The p53 family consists of p53, p63 and p73, which have similar structure and share homology in major domains such as transactivation domain (TA), DNA‐binding domain (DBD), proline‐rich domain (PR) and oligomerization domain (OD). P63 and p73 also contain additional proline‐rich domain (PR) and sterile alpha motif (SAM). The involvement of each member in growth suppression and development is indicated.

Figure 5.

Strategies for activation of p53 in cancer cells. Wild‐type p53 can be activated by inhibition of the interaction between p53 and Mdm2 using Nutlins and RITA. Mutant p53 can be reactivated using small molecules such as CP‐31398, PRIMA‐1 or MIRA. CDB3 is able to shift the equilibrium existing between wild‐type p53 and muatant p53 towards functional p53. P73 chemosensitivity can be restored by exposure to RETRA or 37AA, if its activities are inhibited through sequestration by mutant p53 or is APP, respectively.

close

References

Ambrosini G, Adida C and Altieri DC (1997) A novel anti‐apoptosis gene, survivin, expressed in cancer and lymphoma. Nature Medicine 3: 917–921.

Asher G, Lotem J, Cohen B, Sachs L and Shaul Y (2001) Regulation of p53 stability and p53‐dependent apoptosis by NADH quinone oxidoreductase 1. Proceedings of the National Academy of Sciences of the USA 98: 1188–1193.

Bell HS, Dufes C, O'prey J et al. (2007) A p53‐derived apoptotic peptide derepresses p73 to cause tumor regression in vivo. Journal of Clinical Investigation 117: 1008–1018.

Benard J, Douc‐Rasy S and Ahomadegbe JC (2003) TP53 family members and human cancers. Human Mutation 21: 182–191.

Bergamaschi D, Gasco M, Hiller L et al. (2003) p53 polymorphism influences response in cancer chemotherapy via modulation of p73‐dependent apoptosis. Cancer Cell 3: 387–402.

Bertheau P, Espie M, Turpin E et al. (2008) TP53 status and response to chemotherapy in breast cancer. Pathobiology 75: 132–139.

Bullock AN and Fersht AR (2001) Rescuing the function of mutant p53. Nature Reviews of Cancer 1: 68–76.

Chang NS, Doherty J and Ensign A (2003) JNK1 physically interacts with WW domain‐containing oxidoreductase (WOX1) and inhibits WOX1‐mediated apoptosis. Journal of Biological Chemistry 278: 9195–9202.

El‐Deiry WS (2003) The role of p53 in chemosensitivity and radiosensitivity. Oncogene 22: 7486–7495.

Flores ER, Tsai KY, Crowley D et al. (2002) p63 and p73 are required for p53‐dependent apoptosis in response to DNA damage. Nature 416: 560–564.

Foster BA, Coffey HA, Morin MJ and Rastinejad F (1999) Pharmacological rescue of mutant p53 conformation and function. Science 286: 2507–2510.

Green DR and Kroemer G (2009) Cytoplasmic functions of the tumour suppressor p53. Nature 458: 1127–1130.

Haupt S and Haupt Y (2006) Importance of p53 for cancer onset and therapy. Anticancer Drugs 17: 725–732.

Haupt S, Berger M, Goldberg Z and Haupt Y (2003) Apoptosis: the p53 network. Journal of Cell Science 116: 4077–4085.

Haupt Y, Rowan S, Shaulian E, Vousden KH and Oren M (1995) Induction of apoptosis in HeLa cells by trans‐activation‐deficient p53. Genes & Development 9: 2170–2183.

Hoffman WH, Biade S, Zilfou JT, Chen J and Murphy M (2002) Transcriptional repression of the anti‐apoptotic survivin gene by wild type p53. Journal of Biological Chemistry 277: 3247–3257.

Hwang PM, Bunz F, Yu J et al. (2001) Ferredoxin reductase affects p53‐dependent, 5‐fluorouracil‐induced apoptosis in colorectal cancer cells. Nature Medicine 7: 1111–1117.

Issaeva N, Bozko P, Enge M et al. (2004) Small molecule RITA binds to p53, blocks p53‐HDM‐2 interaction and activates p53 function in tumors. Nature Medicine 10: 1321–1328.

Jin S, Martinek S, Joo WS et al. (2000) Identification and characterization of a p53 homologue in Drosophila melanogaster. Proceedings of the National Academy of Sciences of the USA 97: 7301–7306.

Kastan MB (2007) Wild‐type p53: tumors can't stand it. Cell 128: 837–840.

Kravchenko JE, Ilyinskaya GV, Komarov PG et al. (2008) Small‐molecule RETRA suppresses mutant p53‐bearing cancer cells through a p73‐dependent salvage pathway. Proceedings of the National Academy of Sciences of the USA 105: 6302–6307.

Kuribayashi K, Krigsfeld G, Wang W et al. (2008) TNFSF10 (TRAIL), a p53 target gene that mediates p53‐dependent cell death. Cancer Biology & Therapy 7: 2034–2038.

Lang GA, Iwakuma T, Suh YA et al. (2004) Gain of function of a p53 hot spot mutation in a mouse model of Li‐Fraumeni syndrome. Cell 119: 861–872.

Lavin MF and Gueven N (2006) The complexity of p53 stabilization and activation. Cell Death and Differentiation 13: 941–950.

MacLachlan TK and El‐Deiry WS (2002) Apoptotic threshold is lowered by p53 transactivation of caspase‐6. Proceedings of the National Academy of Sciences of the USA 99: 9492–9497.

Maecker HL, Koumenis C and Giaccia AJ (2000) p53 promotes selection for Fas‐mediated apoptotic resistance. Cancer Research 60: 4638–4644.

Marchenko ND, Zaika A and Moll UM (2000) Death signal‐induced localization of p53 protein to mitochondria. A potential role in apoptotic signaling. Journal of Biological Chemistry 275: 16202–16212.

Marine JC, Dyer MA and Jochemsen AG (2007) MDMX: from bench to bedside. Journal of Cell Science 120: 371–378.

Mayo LD and Donner DB (2002) The PTEN, Mdm2, p53 tumor suppressor‐oncoprotein network. Trends n Biochemical Science 27: 462–467.

Mckeon F and Melino G (2007) Fog of war: the emerging p53 family. Cell Cycle 6: 229–232.

Meulmeester E and Jochemsen AG (2008) p53: a guide to apoptosis. Current Cancer Drug Targets 8: 87–97.

Nakamizo A, Amano T, Zhang W et al. (2008) Phosphorylation of Thr18 and Ser20 of p53 in Ad‐p53‐induced apoptosis. Neuro‐Oncology 10(3): 275–291.

Olive KP, Tuveson DA, Ruhe ZC et al. (2004) Mutant p53 gain of function in two mouse models of Li‐Fraumeni syndrome. Cell 119: 847–860.

Olivier M, Petitjean A, Marcel V et al. (2009) Recent advances in p53 research: an interdisciplinary perspective. Cancer Gene Therapy 16: 1–12.

Polyak K, Xia Y, Zweier JL, Kinzler KW and Vogelstein B (1997) A model for p53‐induced apoptosis. Nature 389: 300–305.

Pratt MA, White D, Kushwaha N, Tibbo E and Niu MY (2007) Cytoplasmic mutant p53 increases Bcl‐2 expression in estrogen receptor‐positive breast cancer cells. Apoptosis 12: 657–669.

Pritchard DM, Potten CS, Korsmeyer SJ, Roberts S and Hickman JA (1999) Damage‐induced apoptosis in intestinal epithelia from bcl‐2‐null and bax‐null mice: investigations of the mechanistic determinants of epithelial apoptosis in vivo. Oncogene 18: 7287–7293.

Royds JA and Iacopetta B (2006) p53 and disease: when the guardian angel fails. Cell Death and Differentiation 13: 1017–1026.

Sax JK, Fei P, Murphy ME et al. (2002) BID regulation by p53 contributes to chemosensitivity. Nature Cell Biology 4: 842–849.

Schumacher B, Hofmann K, Boulton S and Gartner A (2001) The C. elegans homolog of the p53 tumor suppressor is required for DNA damage‐induced apoptosis. Current Biology 11: 1722–1727.

Sharpless NE (2005) INK4a/ARF: a multifunctional tumor suppressor locus. Mutation Research 576: 22–38.

Terzian T, Suh YA, Iwakuma T et al. (2008) The inherent instability of mutant p53 is alleviated by Mdm2 or p16INK4a loss. Genes & Development 22: 1337–1344.

Toledo F and Wahl GM (2006) Regulating the p53 pathway: in vitro hypotheses, in vivo veritas. Nature Reviews of Cancer 6: 909–923.

Tomasini R, Tsuchihara K, Wilhelm M et al. (2008) TAp73 knockout shows genomic instability with infertility and tumor suppressor functions. Genes & Development 22: 2677–2691.

Villunger A, Michalak EM, Coultas L et al. (2003) p53‐ and drug‐induced apoptotic responses mediated by BH3‐only proteins puma and noxa. Science 302: 1036–1038.

Vousden KH and Lane DP (2007) p53 in health and disease. Nature Reviews. Molecular Cellular Biology 8: 275–283.

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

Wang W, Takimoto R, Rastinejad F and El‐Deiry WS (2003) Stabilization of p53 by CP‐31398 inhibits ubiquitination without altering phosphorylation at serine 15 or 20 or MDM2 binding. Molecular and Cellular Biology 23: 2171–2181.

Wu Y, Mehew JW, Heckman CA, Arcinas M and Boxer LM (2001) Negative regulation of bcl‐2 expression by p53 in hematopoietic cells. Oncogene 20: 240–251.

Yonish‐Rouach E, Resnitzky D, Lotem J et al. (1991) Wild‐type p53 induces apoptosis of myeloid leukaemic cells that is inhibited by interleukin‐6. Nature 352: 345–347.

Further Reading

Campisi J and D'adda Di Fagagna F (2007) Cellular senescence: when bad things happen to good cells. Nature Reviews. Molecular Cellular Biology 8(9): 729–740.

Michalak E, Villunger A, Erlacher M and Strasser A (2005) Death squads enlisted by the tumour suppressor p53. Biochemical and Biophysical Research Communications 331(3): 786–798.

Peters G and Vousden KH (eds) (1997) Oncogenes and Tumour Suppressors. Oxford: Oxford University Press.

Riley T, Sonatg E, Chen P and Levine A (2008) Transcriptional control of p53‐regulated genes. Nature Reviews of Molecualr and Cellular Biology 9(5): 402–412.

Weinberg R (2007) Biology of cancer. New York, London: Garland Science Press.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Wolyniec, Kamil, Haupt, Sue, and Haupt, Ygal(Dec 2009) P53 and Cell Death. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0021824]