The tumour suppressor, p53, is recognized as a crucial molecule in regulating cellular responses to various DNA-damaging agents. Very early on in the development of nonmelanoma cancers p53 is mutated or lost, suggesting that p53 is crucial in protecting normal keratinocytes from the harmful effects of ultraviolet (UV) radiation.
Objective:
Using two mouse models, one with multiple copies of mutant p53 and the other a p53 “knockout,” our laboratory has examined a role for p53 in UV-induced DNA damage and determined if these effects are differentiation dependent.
Conclusion:
We outline in this review a proposed model reflecting differentiation-dependent p53 regulation of UV-induced responses in keratinocytes. After exposure to UV, basal keratinocytes repair damaged DNA, whereas differentiating keratinocytes undergo cell death, both processes are regulated by p53.
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References
1.
MurphyGE, Histology of the skin. In: ElderD, ed. Histopathology of the skin. Philadelphia, PA: Lippincott-Raven, 1997:5–11.
2.
MorrisRJFischerSMSlagaTJ. Evidence that a slowly cycling subpopulation of adult murine epidermal cells retains carcinogen. Cancer Res1986; 46:3061–3066.
3.
MorrisRJCoulterKTrysonK. Evidence that cutaneous carcinogen-initiated epithelial cells from mice are quiescent rather than actively cycling. Cancer Res1997; 57:3436–3443.
4.
KastanMBOnyineOSidranskyD. Participation of p53 protein in the cellular response to DNA damage. Cancer Res1991; 51:6304–6311.
5.
KastanMBZhanQEl-DeiryWS. A mammalian cell cycle checkpoint pathway utilizing p53 and GADD45 is defective in ataxia-telangiectasia. Cell1992; 71:587–597.
6.
FordJMHanawaltPC. Li-Fraumeni syndrome fibroblasts homozygous for p53 mutations are deficient in global DNA repair but exhibit normal transcription-coupled repair and enhanced UV resistance. Proc Natl Acad Sci U S A1995; 92:8876–8880.
7.
LoweSWSchmittEMSmithSW. p53 is required for radiation-induced apoptosis in mouse thymocytes. Nature1993; 362:847–849.
8.
BrashDERudolphJASimonJA. A role for sunlight in skin cancer: UV-induced p53 mutations in squamous cell carcinoma. Proc Natl Acad Sci U S A1991; 88:10124–10128.
9.
ZieglerAJonasonASLeffellDJ. Sunburn and p53 in the onset of skin cancer. Nature1994; 372:773–776.
10.
LiGHoVCBereanK. Ultraviolet radiation induction of squamous cell carcinomas in p53 transgenic mice. Cancer Res1995; 55:2070–2074.
11.
LiGTronVHoV. Induction of squamous cell carcinoma in p53-deficient mice after ultraviolet irradiation. J Invest Dermatol1998; 110:72–75.
12.
DonehowerLAHarveyMSlagleBL. Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature1992; 356:215–221.
13.
SmithMLChenITZhanQ. Involvement of the p53 tumour suppressor in repair of u.v.-type DNA damage. Oncogene1995; 10:1053–1059.
14.
LiGMitchellDLHoVC. Decreased DNA repair but normal apoptosis in ultraviolet-irradiated skin of p53-transgenic mice. Am J Pathol1996; 148:1113–1123.
15.
LiGHoVCMitchellDL. Differentiation-dependent p53 regulation of nucleotide excision repair in keratinocytes. Am J Pathol1997; 150:1457–1464.
16.
TronVATrotterMJIshikawaT. p53-Dependent regulation of nucleotide excision repair in murine epidermis in vivo. J Cutan Med Surg1998; 3:16–20.
17.
FornaceAJNebertDWHollanderMC. Mammalian genes coordinately regulated by growth arrest signals and DNA-damaging agents. Mol Cell Biol1989; 9:4196–4203.
18.
XiongYHannonGJZhangH. p21 is a universal inhibitor of cyclin kinases. Nature1993; 366:701–704.
19.
ZhanQBaeIKastanMB. The p53-dependent gammaray response of GADD45. Cancer Res1994; 54:2755–2760.
20.
ZhanQCarrierFFornaceAJ. Induction of cellular p53 activity by DNA-damaging agents and growth arrest. Mol Cell Biol1993; 13:4242–4250.
21.
SmithMLChenIZhanQ. Interaction of the p53-regulated protein Gadd45 with proliferating cell nuclear antigen. Science1994; 266:1376–1380.
22.
SmithMLKontnyHUZhanQ. Antisense GADD45 expression results in decreased DNA repair and sensitizes cells to UV-irradiation or cisplatin. Oncogene1996; 13:2255–2263.
23.
El-DeiryWSTokinoTVelculescuVE. WAF-1, a potential mediator of p53 tumour suppression. Cell1993; 75:817–825.
24.
HarperJWAdamGRWeiN. The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell1993; 75:805–816.
25.
MacdonaldERWuGSWaldmanT. Repair defect in p21 WAF1/CIP1 −/− human cancer cells. Cancer Res1996; 56:2250–2255.
26.
FanSChangJKSmithML. Cells lacking CIP1/Waf1 genes exhibit preferential sensitivity of cisplatin and nitrogen mustard. Oncogene1997; 14:2127–2136.
27.
PanZReardonJTLiL. Inhibition of nucleotide excision repair by the cyclin-dependent kinase inhibitor p21. J Biol Chem1995;270:22008–22016.
28.
LiRWigaSHannonGJ. Differential effects by the p21 CDK inhibitor on PCNA-dependent DNA replication and repair. Nature1994; 371:534–537.
29.
WangXWForresterKYehH. Hepatitis B virus X protein inhibits p53 sequence-specific DNA binding, transcriptional activity, and association with transcription factor ERCC3. Proc Natl Acad Sci U S A1994; 91:2230–2234.
LoignonMFetniRGordonAJE. A p53-independent pathway for induction of pH21waf1cip1 and concomitant G1 arrest in UV-irradiated human skin fibroblasts. Cancer Res1997; 57: 3390–3394.
32.
ZengYXEl-DeiryWS. Regulation of p21WAF1/CIP1 expression by p53-independent pathways. Oncogene1996; 12: 1557–1564.
33.
TronVATangLYongWP. Differentiation-associated overexpression of the cyclin-dependent kinase inhibitor p21waf-1 in human cutaneous squamous cell carcinoma. Am J Pathol1996; 149:1139–1146.
34.
TronVATrotterMJTangI. p53-Regulated apoptosis is differentiation-dependent in UVB irradiated mouse keratinocytes. Am J Pathol1998; 153:579–585.
35.
GilchrestBASoterNAStoffJS. The human sunburn reaction: Histologic and biochemical studies. J Am Acad Dermatol1981; 5:411–422.
MiyashitaTReedJC. Tumour suppressor p53 is a direct transcriptional activator of the human bax gene. Cell1995; 80:293–299.
38.
MiyashitaTKrajewskiSKrajewskaM. Tumour suppressor p53 is a regulator of bcl-2 and bax gene expression in vitro and in vivo. Oncogene1994; 9:1799–1805.
39.
WolfDHarrisNGoldfingerN. Isolation of full-length mouse cDNA clone coding for an immunologically distinct p53 molecule. Mol Cell Biol1985; 5:127–132.
40.
WuLBayleJHElenbaasB. Alternatively spliced forms in the carboxy-terminal domain of the p53 protein regulate its ability to promote annealing of complementary single strands of nucleic acids. Mol Cell Biol1995; 15:497–504.
41.
Kulesz-MartinMFLisafeldBHuangH. Endogenous p53 protein generated form wild-type alternatively spliced p53 in mouse epidermal cells. Mol Cell Biol1994; 14:1698–1708.
42.
RehbergerPARichterKHSchwartzD. Differential expression of the regularly spliced wild-type p53 and its COOH-terminal alternatively spliced form during epidermal differentiation. Cell Growth Differ1997; 8:851–860.
43.
WeinbergWCAzzoliCGChapmanK. p53-Mediated transcriptional activity increases in differentiating epidermal keratinocytes in association with decreased p53 protein. Oncogene1995; 10:2271–2279.
