Sunburn and p53 in the onset of skin cancer

Abstract

Squamous cell carcinoma of the skin (SCC) can progress by stages: sun-damaged epidermis, with individual disordered keratinocytes; actinic keratosis (AK), spontaneously regressing keratinized patches having aberrant cell differentiation and proliferation; carcinoma in situ; SCC and metastasis. To understand how sunlight acts as a carcinogen, we determined the stage at which sunlight mutates the p53 tumour-suppressor gene and identified a function for p53 in skin. The p53 mutations induced by ultraviolet radiation and found in > 90% of human SCCs were present in AKs. Inactivating p53 in mouse skin reduced the appearance of sunburn cells, apoptotic keratinocytes generated by overexposure to ultraviolet. Skin thus appears to possess a p53-dependent 'guardian-of-the-tissue' response to DNA damage which aborts precancerous cells. If this response is reduced in a single cell by a prior p53 mutation, sunburn can select for clonal expansion of the p53-mutated cell into the AK. Sunlight can act twice: as tumour initiator and tumour promoter.

Twenty years of p53 research: structural and functional aspects of the p53 protein

“…If p53 is mutated or inactivated in some manner, the apoptotic response is not activated and cell proliferation is allowed. Analysis of cells and tissues of p53-null mice has shown that functional p53 is necessary for DNA damage-induced apoptosis of cortical thymocytes (Clarke et al, 1993), myeloid progenitor cells (Lotem and Sachs, 1993), marrow preB cells (Strasser et al, 1994), quiescent peripheral B and T lymphocytes (Strasser et al, 1994), keratinocytes (Ziegler et al, 1994) and small intestine cells .…”

Mutant p53 subverts p63 control over KLF4 expression in keratinocytes

“…However, the p53 missense mutations harbored by HaCaT alleles are indeed UVB signature mutations (Pfeifer and Besaratinia, 2009, and references therein). Two apparently contradictory results blur our vision as to the role of p53 in skin cancer: mice deficient for TP53 develop tumors resembling SCC after UV irradiation (Ziegler et al, 1994;Li et al, 1998;Jiang et al, 1999), whereas Li-Fraumeni syndrome patients, who have a germline mutation in TP53, are not reported to be at increased risk for SCC (Malkin et al, 1990). These findings should be put in the perspective of the growing body of evidence showing that p53 missense mutants not only lose normal p53 functions, but are also often pro-active in tumor formation (reviewed by Donzelli et al, 2008;Brosh and Rotter, 2009).…”

Does Notch play a tumor suppressor role across diverse squamous cell carcinomas?

“…p53 is also an established cancer gene in CSCC 40, 41, 42 and HNSCC 43. Although p53 levels in cutaneous SCC are less characterized, somatic mutations of TP53 are frequently found in many typical tumors including CSCCs, which is then likely to compromise p53 function 44.…”