Skin Cancers Caused by UV Acting on the Rb Pathway

A recent study has revealed that the mechanism by which the sun's ultraviolet light stimulates the formation of skin cancer requires an intact Rb pathway. The results were reported in the February 4, 2003, issue of the Proceedings of the National Academy of Sciences.

The term "Rb pathway” refers to the gene (RB1) for the retinoblastoma protein, pRb, which was the first mammalian tumor suppressor gene to be isolated. Data generated in the last decade have pointed to a crucial role for pRb in the regulation of fundamental cellular processes such as differentiation, proliferation and apoptosis. Genetic and biochemical data have placed pRb in a linear pathway. This pathway involves cyclin- dependent kinase (CDK) inhibitors of the INK4 family, which act as negative regulators of cell proliferation, and the positively acting D-type cyclins that in association with CDK4 or CDK6 form active kinase complexes. The downstream targets in the pathway are the E2F transcription factors.


The majority of human cancers harbor alterations in one of the genes in the pRb pathway as a result of an inactivating germline or somatic mutations in RB1 or p16INK4A, activating mutations in CDK4, and amplification or overexpression of the D-type cyclins and CDK4 or CDK6.

Investigators from the Dana-Farber Cancer Institute (Boston, MA, USA) exposed newborns of two strains of genetically engineered mice--one lacking a critical component of the p53 pathway, p19, and one lacking the Rb pathway protein p16--to UV radiation. (Both strains carried the Ras mutation, making them especially cancer-prone.) The p19 mutants, whose Rb pathway was intact, had a much higher chance of developing melanomas when exposed to UV radiation—85% compared to 50% in nonexposed litters. They also developed more tumors, two to three compared to one in the non-exposed group, and the lesions appeared, on average, six weeks sooner.

"It looks like the Rb pathway is specifically targeted by ultraviolet radiation,” explained senior author Dr. Lynda Chin, assistant professor of dermatology at Harvard Medical School. "If you see in a sun-induced lesion that its Rb pathway has been inactivated, then the risk of it becoming a melanoma is much greater than one without such a lesion. You could then use that as a prognostic factor to determine which of these funny-looking moles needs to be cut out with a wide margin around it.”



Related Links:
Dana-Farber Cancer Institute