Unravelling Mechanisms of P53-mediated Tumour Suppression

Overview

Journal Nat Rev Cancer

Specialty Oncology

Date 2014 Apr 18

PMID 24739573

Citations 724

Authors

Kathryn T Bieging

Stephano Spano Mello

Laura D Attardi

Affiliations

Soon will be listed here.

Abstract

p53 is a crucial tumour suppressor that responds to diverse stress signals by orchestrating specific cellular responses, including transient cell cycle arrest, cellular senescence and apoptosis, which are all processes associated with tumour suppression. However, recent studies have challenged the relative importance of these canonical cellular responses for p53-mediated tumour suppression and have highlighted roles for p53 in modulating other cellular processes, including metabolism, stem cell maintenance, invasion and metastasis, as well as communication within the tumour microenvironment. In this Opinion article, we discuss the roles of classical p53 functions, as well as emerging p53-regulated processes, in tumour suppression.

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References

Valente L, Gray D, Michalak E, Pinon-Hofbauer J, Egle A, Scott C . p53 efficiently suppresses tumor development in the complete absence of its cell-cycle inhibitory and proapoptotic effectors p21, Puma, and Noxa. Cell Rep. 2013; 3(5):1339-45. DOI: 10.1016/j.celrep.2013.04.012. View

Maddocks O, Vousden K . Metabolic regulation by p53. J Mol Med (Berl). 2011; 89(3):237-45. PMC: 3043245. DOI: 10.1007/s00109-011-0735-5. View

Malkin D, Li F, Strong L, Fraumeni Jr J, Nelson C, Kim D . Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science. 1990; 250(4985):1233-8. DOI: 10.1126/science.1978757. View

Feldser D, Kostova K, Winslow M, Taylor S, Cashman C, Whittaker C . Stage-specific sensitivity to p53 restoration during lung cancer progression. Nature. 2010; 468(7323):572-5. PMC: 3003305. DOI: 10.1038/nature09535. View

Tron V, Trotter M, Ishikawa T, Ho V, Li G . p53-dependent regulation of nucleotide excision repair in murine epidermis in vivo. J Cutan Med Surg. 1998; 3(1):16-20. DOI: 10.1177/120347549800300104. View

Donehower L, Harvey M, Slagle B, McArthur M, Montgomery Jr C, Butel J . Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature. 1992; 356(6366):215-21. DOI: 10.1038/356215a0. View

Gaiddon C, Lokshin M, Ahn J, Zhang T, Prives C . A subset of tumor-derived mutant forms of p53 down-regulate p63 and p73 through a direct interaction with the p53 core domain. Mol Cell Biol. 2001; 21(5):1874-87. PMC: 86759. DOI: 10.1128/MCB.21.5.1874-1887.2001. View

Matoba S, Kang J, Patino W, Wragg A, Boehm M, Gavrilova O . p53 regulates mitochondrial respiration. Science. 2006; 312(5780):1650-3. DOI: 10.1126/science.1126863. View

Hill R, Song Y, Cardiff R, Van Dyke T . Selective evolution of stromal mesenchyme with p53 loss in response to epithelial tumorigenesis. Cell. 2005; 123(6):1001-11. DOI: 10.1016/j.cell.2005.09.030. View

10.

Heinlein C, Krepulat F, Lohler J, Speidel D, Deppert W, Tolstonog G . Mutant p53(R270H) gain of function phenotype in a mouse model for oncogene-induced mammary carcinogenesis. Int J Cancer. 2007; 122(8):1701-9. DOI: 10.1002/ijc.23317. View

11.

Hollander M, Philburn R, Patterson A, Velasco-Miguel S, Friedberg E, Linnoila R . Deletion of XPC leads to lung tumors in mice and is associated with early events in human lung carcinogenesis. Proc Natl Acad Sci U S A. 2005; 102(37):13200-5. PMC: 1201581. DOI: 10.1073/pnas.0503133102. View

12.

Hu W, Feng Z, Levine A . The Regulation of Multiple p53 Stress Responses is Mediated through MDM2. Genes Cancer. 2012; 3(3-4):199-208. PMC: 3494373. DOI: 10.1177/1947601912454734. View

13.

Christophorou M, Ringshausen I, Finch A, Swigart L, Evan G . The pathological response to DNA damage does not contribute to p53-mediated tumour suppression. Nature. 2006; 443(7108):214-7. DOI: 10.1038/nature05077. View

14.

Brady C, Attardi L . p53 at a glance. J Cell Sci. 2010; 123(Pt 15):2527-32. PMC: 2912460. DOI: 10.1242/jcs.064501. View

15.

Tront J, Hoffman B, Liebermann D . Gadd45a suppresses Ras-driven mammary tumorigenesis by activation of c-Jun NH2-terminal kinase and p38 stress signaling resulting in apoptosis and senescence. Cancer Res. 2006; 66(17):8448-54. DOI: 10.1158/0008-5472.CAN-06-2013. View

16.

Rowan S, Ludwig R, Haupt Y, Bates S, Lu X, Oren M . Specific loss of apoptotic but not cell-cycle arrest function in a human tumor derived p53 mutant. EMBO J. 1996; 15(4):827-38. PMC: 450281. View

17.

Marion R, Strati K, Li H, Murga M, Blanco R, Ortega S . A p53-mediated DNA damage response limits reprogramming to ensure iPS cell genomic integrity. Nature. 2009; 460(7259):1149-53. PMC: 3624089. DOI: 10.1038/nature08287. View

18.

Chehab N, Malikzay A, Stavridi E, Halazonetis T . Phosphorylation of Ser-20 mediates stabilization of human p53 in response to DNA damage. Proc Natl Acad Sci U S A. 1999; 96(24):13777-82. PMC: 24141. DOI: 10.1073/pnas.96.24.13777. View

19.

Junttila M, Karnezis A, Garcia D, Madriles F, Kortlever R, Rostker F . Selective activation of p53-mediated tumour suppression in high-grade tumours. Nature. 2010; 468(7323):567-71. PMC: 3011233. DOI: 10.1038/nature09526. View

20.

Miller L, Smeds J, George J, Vega V, Vergara L, Ploner A . An expression signature for p53 status in human breast cancer predicts mutation status, transcriptional effects, and patient survival. Proc Natl Acad Sci U S A. 2005; 102(38):13550-5. PMC: 1197273. DOI: 10.1073/pnas.0506230102. View