Gain‐of‐Function Mutants of p53 and Their Role in Tumourigenesis


The p53 gene is a tumour suppressor that is widely mutated in human cancers. Wild‐type p53 plays a pivotal role in preventing deoxyribonucleic acid (DNA) damage and maintaining the integrity of the cell. Cells that contain mutant p53, however, are unable to prevent this damage and, in fact, become more oncogenic. Gain‐of‐function (GOF) mutant p53 has been shown to transactivate a number of genes that are part of cell growth and survival pathways and cause an increase in tumourigenicity. Knockin and transgenic mouse models have been utilised to explore the GOF phenotype of mutant p53. Currently, p53 cannot be targeted for cancer therapy, but recent studies have demonstrated the ability to reduce tumourigenicity in lung cancer cells addicted to their endogenous GOF mutant p53.

Key Concepts:

  • The p53 gene is the most frequently mutated tumour suppressor gene in cancer.

  • WT p53 plays an active role in the cell cycle, DNA repair, apoptosis, and can function as a transcriptional activator.

  • A wide array of functions of WT p53 are dependent on its transcriptional ability.

  • Gain‐of‐function mutations are characterised by loss of the wild‐type tumour suppressor functions of p53 as well as gain of new oncogenic functions.

  • Several groups have utilized mouse models to study mutant p53 gain of function in cancer.

Keywords: mutant; p53; transactivation; oncogenesis; gain of function

Figure 1.

Schematic of p53 protein indicating several mutations within the DNA‐binding domain.



Adorno M, Cordenonsi M, Montagner M et al. (2009) A mutant‐p53/Smad complex opposes p63 to empower TGFbeta‐induced metastasis. Cell 137: 87–98.

Allred DC, Clark GM, Elledge R et al. (1993) Association of p53 protein expression with tumor cell proliferation rate and clinical outcome in node‐negative breast cancer. Journal of the National Cancer Institute 85: 200–206.

Aylon Y and Oren M (2011) p53: guardian of ploidy. Molecular Oncology 5: 315–323.

Beckerman R and Prives C (2010) Transcriptional regulation by p53. Cold Spring Harbor Perspectives in Biology 2: a000935.

Borellini F and Glazer RI (1993) Induction of Sp1‐p53 DNA‐binding heterocomplexes during granulocyte/macrophage colony‐stimulating factor‐dependent proliferation in human erythroleukemia cell line TF‐1. Journal of Biological Chemistry 268: 7923–7928.

Chin KV, Ueda K, Pastan I and Gottesman MM (1992) Modulation of activity of the promoter of the human MDR1 gene by Ras and p53. Science 255: 459–462.

Deb S, Jackson CT, Subler MA and Martin DW (1992) Modulation of cellular and viral promoters by mutant human p53 proteins found in tumor cells. Journal of Virology 66: 6164–6170.

el‐Deiry WS, Kern SE, Pietenpol JA, Kinzler KW and Vogelstein B (1992) Definition of a consensus binding site for p53. Nature Genetics 1: 45–49.

Di Agostino S, Strano S, Emiliozzi V et al. (2006) Gain of function of mutant p53: the mutant p53/NF‐Y protein complex reveals an aberrant transcriptional mechanism of cell cycle regulation. Cancer Cell 10: 191–202.

Dittmer D, Pati S, Zambetti G et al. (1993) Gain of function mutations in p53. Nature Genetics 4: 42–46.

Fogal V, Hsieh JK, Royer C, Zhong S and Lu X (2005) Cell cycle‐dependent nuclear retention of p53 by E2F1 requires phosphorylation of p53 at Ser315. Embo Journal 24: 2768–2782.

Freed‐Pastor WA and Prives C (2012) Mutant p53: one name, many proteins. Genes and Development 26: 1268–1286.

Funk WD, Pak DT, Karas RH, Wright WE and Shay JW (1992) A transcriptionally active DNA‐binding site for human p53 protein complexes. Molecular and Cellular Biology 12: 2866–2871.

Giebler HA, Lemasson I and Nyborg JK (2000) p53 recruitment of CREB binding protein mediated through phosphorylated CREB: a novel pathway of tumor suppressor regulation. Molecular and Cellular Biology 20: 4849–4858.

Ginsberg D, Mechta F, Yaniv M and Oren M (1991) Wild‐type p53 can down‐modulate the activity of various promoters. Proceedings of the National Academy of Sciences of the USA 88: 9979–9983.

Hanel W, Marchenko N, Xu S et al. (2013) Two hot spot mutant p53 mouse models display differential gain of function in tumorigenesis. Cell Death and Differentiation 20(7): 898–909.

Heinlein C, Krepulat F, Lohler J et al. (2008) Mutant p53(R270H) gain of function phenotype in a mouse model for oncogene‐induced mammary carcinogenesis. International Journal of Cancer 122: 1701–1709.

Hermeking H (2012) MicroRNAs in the p53 network: micromanagement of tumour suppression. Nature Reviews Cancer 12: 613–626.

Lanyi A, Deb D, Seymour RC et al. (1998) ‘Gain of function’ phenotype of tumor‐derived mutant p53 requires the oligomerization/nonsequence‐specific nucleic acid‐binding domain. Oncogene 16: 3169–3176.

Lee CW, Ferreon JC, Ferreon AC, Arai M and Wright PE (2010) Graded enhancement of p53 binding to CREB‐binding protein (CBP) by multisite phosphorylation. Proceedings of the National Academy of Sciences of the USA 107: 19290–19295.

Lin J, Teresky AK and Levine AJ (1995) Two critical hydrophobic amino acids in the N‐terminal domain of the p53 protein are required for the gain of function phenotypes of human p53 mutants. Oncogene 10: 2387–2390.

Liu G, Parant JM, Lang G et al. (2004) Chromosome stability, in the absence of apoptosis, is critical for suppression of tumorigenesis in Trp53 mutant mice. Nature Genetics 36: 63–68.

Maddocks OD and Vousden KH (2011) Metabolic regulation by p53. Journal of Molecular Medicine 89: 237–245.

Martin DW, Munoz RM, Subler MA and Deb S (1993) p53 binds to the TATA‐binding protein‐TATA complex. Journal of Biological Chemistry 268: 13062–13067.

Menendez D, Nguyen TA, Freudenberg JM et al. (2013) Diverse stresses dramatically alter genome‐wide p53 binding and transactivation landscape in human cancer cells. Nucleic Acids Research 41(15): 7286–7301.

Oren M and Rotter V (2010) Mutant p53 gain‐of‐function in cancer. Cold Spring Harbor Perspectives in Biology 2: a001107.

Pietenpol JA, Tokino T, Thiagalingam S et al. (1994) Sequence‐specific transcriptional activation is essential for growth suppression by p53. Proceedings of the National Academy of Sciences of the USA 91: 1998–2002.

Prives C and Hall PA (1999) The p53 pathway. Journal of Pathology 187: 112–126.

Reinhardt HC and Schumacher B (2012) The p53 network: cellular and systemic DNA damage responses in aging and cancer. Trends in Genetics 28: 128–136.

Ryan KM (2011) p53 and autophagy in cancer: guardian of the genome meets guardian of the proteome. European Journal of Cancer 47: 44–50.

Sahin E and DePinho RA (2012) Axis of ageing: telomeres, p53 and mitochondria. Nature Reviews Molecular Cell Biology 13: 397–404.

Sampath J, Sun D, Kidd VJ et al. (2001) Mutant p53 cooperates with ETS and selectively up‐regulates human MDR1 not MRP1. Journal of Biological Chemistry 276: 39359–39367.

Schilling T, Kairat A, Melino G et al. (2010) Interference with the p53 family network contributes to the gain of oncogenic function of mutant p53 in hepatocellular carcinoma. Biochemical and Biophysical Research Communications 394: 817–823.

Scian MJ, Stagliano KE, Anderson MA et al. (2005) Tumor‐derived p53 mutants induce NF‐kappaB2 gene expression. Molecular and Cellular Biology 25: 10097–10110.

Seto E, Usheva A, Zambetti GP et al. (1992) Wild‐type p53 binds to the TATA‐binding protein and represses transcription. Proceedings of the National Academy of Sciences of the USA 89: 12028–12032.

Subler MA, Martin DW and Deb S (1992) Inhibition of viral and cellular promoters by human wild‐type p53. Journal of Virology 66: 4757–4762.

Tan EH, Morton JP, Timpson P et al. (2013) Functions of TAp63 and p53 in restraining the development of metastatic cancer. Oncogene.

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

Trinidad AG, Muller PA, Cuellar J et al. (2013) Interaction of p53 with the CCT complex promotes protein folding and wild‐type p53 activity. Molecular Cell 50: 805–817.

Vaughan CA, Frum R, Pearsall I et al. (2012) Allele specific gain‐of‐function activity of p53 mutants in lung cancer cells. Biochemical and Biophysical Research Communications 428: 6–10.

Vikhanskaya F, Lee MK, Mazzoletti M, Broggini M and Sabapathy K (2007) Cancer‐derived p53 mutants suppress p53‐target gene expression – Potential mechanism for gain of function of mutant p53. Nucleic Acids Research 35: 2093–2104.

Vilborg A, Bersani C, Wilhelm MT and Wiman KG (2011) The p53 target Wig‐1: a regulator of mRNA stability and stem cell fate? Cell Death and Differentiation 18: 1434–1440.

Wang XJ, Greenhalgh DA, Jiang A et al. (1998) Analysis of centrosome abnormalities and angiogenesis in epidermal‐targeted p53172H mutant and p53‐knockout mice after chemical carcinogenesis: evidence for a gain of function. Molecular Carcinogenesis 23: 185–192.

Wang Y, Kong N, Li N et al. (2013) Epidermal growth factor receptor signaling‐dependent calcium elevation in cumulus cells is required for NPR2 inhibition and meiotic resumption in mouse oocytes. Endocrinology 154(9): 3401–3409.

Weinstein IB (2002) Cancer. Addiction to oncogenes – The Achilles heal of cancer. Science 297: 63–64.

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

Wilkinson DS, Tsai WW, Schumacher MA and Barton MC (2008) Chromatin‐bound p53 anchors activated Smads and the mSin3A corepressor to confer transforming‐growth‐factor‐beta‐mediated transcription repression. Molecular and Cellular Biology 28: 1988–1998.

Yan W, Liu G, Scoumanne A and Chen X (2008) Suppression of inhibitor of differentiation 2, a target of mutant p53, is required for gain‐of‐function mutations. Cancer Research 68: 6789–6796.

Further Reading

Blandino G, Levine AJ and Oren M (1999) Mutant p53 gain of function: differential effects of different p53 mutants on resistance of cultured cells to chemotherapy. Oncogene 18(2): 477–485.

Deb D, Scian M, Roth KE et al. (2002) Hetero‐oligomerization does not compromise ‘gain of function’ of tumor‐derived p53 mutants. Oncogene 21(2): 176–189.

Grossman SR (2001) p300/CBP/p53 interaction and regulation of the p53 response. European Journal of Biochemistry 268(10): 2773–2778.

Lane DP and Crawford LV (1979) T antigen is bound to a host protein in SV40‐transformed cells. Nature 278(5701): 261–263.

Levine AJ, Wu MC, Chang A et al. (1995) The spectrum of mutations at the p53 locus. Evidence for tissue‐specific mutagenesis, selection of mutant alleles, and a ‘gain of function’ phenotype. Annals of the New York Academy of Sciences 768: 111–128.

Martin DW, Subler MA, Muñoz RM et al. (1993) p53 and SV40 T antigen bind to the same region overlapping the conserved domain of the TATA‐binding protein. Biochemical and Biophysical Research Communications 195(1): 428–434.

Scian MJ, Stagliano KE, Ellis MA et al. (2004) Modulation of gene expression by tumor‐derived p53 mutants. Cancer Research 64(20): 7447–7454.

Torti D and Trusolino L (2011) Oncogene addiction as a foundational rationale for targeted anti‐cancer therapy: promises and perils. EMBO Molecular Medicine 3(11): 623–636.

Vaughan CA, Singh S, Windle B et al. (2012) p53 mutants induce transcription of NF‐kappaB2 in H1299 cells through CBP and STAT binding on the NF‐kappaB2 promoter and gain of function activity. Archives of Biochemistry and Biophysics 518(1): 79–88.

Yeudall WA, Vaughan CA, Miyazaki H et al. (2012) Gain‐of‐function mutant p53 upregulates CXC chemokines and enhances cell migration. Carcinogenesis 33(2): 442–451.

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Vaughan, Catherine A, Deb, Swati P, and Deb, Sumitra(Feb 2014) Gain‐of‐Function Mutants of p53 and Their Role in Tumourigenesis. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0022449]