How disruption of cell cycle regulating genes might predispose to sun-induced skin cancer.
The Ink4a/Arf (CDKN2a) locus encodes two proteins that regulate two of the most important tumor suppressor pathways represented by p53 and Rb.(1) Loss of either p16(INK4a) or p19(ARF) was recently reported to reduce the ability of mouse cells to repair UV-induced DNA damage and to induce a UV-mutator phenotype. This observation was independent of cell cycle effects incurred by either p16(INK4a) and/or p19(ARF) loss, as it was demonstrable in unirradiated cells using UV-treated DNA. We suggest that this might explain why germ line mutations of INK4a/ARF predispose mainly to malignant melanoma, a UV-induced skin cancer, and provides a molecular explanation for the link between melanomagenesis and impaired DNA repair. It also further demonstrates that regulation of cell cycle check points and DNA repair in response to genomic insults, such as ultraviolet irradiation are intricately interwoven processes. Differences in the apoptotic response to ultraviolet light between melanocytes and keratinocytes might explain why INK4a/ARF mutations predispose to malignant melanoma, but not to keratinocyte-derived skin cancers.
Rünger
Thomas M
TM
Department of Dermatology, Boston University School of Medicine, Boston, Massachusetts 02118, USA. truenger@bu.edu
Vergilis
Irene
I
Sarkar
Papri
P
DePinho
Ronald A
RA
Sharpless
Norman E
NE
D000818:Animals; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000528:radiation effects; D004260:DNA Repair; D015972:Gene Expression Regulation, Neoplastic; D016161:Genes, Retinoblastoma; D018816:Genes, cdc; D019942:Genes, p16; D016158:Genes, p53; D020022:Genetic Predisposition to Disease; D006801:Humans; D008545:Melanoma / Q000209:etiology* / Q000235:genetics; D009154:Mutation; D012867:Skin / Q000528:radiation effects; D012878:Skin Neoplasms / Q000209:etiology* / Q000235:genetics; D014466:Ultraviolet Rays / Q000009:adverse effects*