ras activity and cyclin D1 expression: An essential mechanism of mouse skin tumor development

ras is a family of small GTP-binding proteins that transduce signals from t yrosine-kinase receptors to the nucleus and thus play a role in the regulat ion of cell proliferation and differentiation. Several lines of evidence ha ve shown that the cell-cycle machinery, specifically the circuit cyclin D1/ cyclin-dependent kinase (cdk) 4 and 6-p16-pRb, lies downstream of ras. Poin t mutations that activate the ras protein and its downstream cascade have b een observed in human and experimental tumors. In particular, I-as mutation s have been well characterized in the mouse skin two-stage carcinogenesis m odel, and a large body of literature has indicated that initiation with the genotoxic carcinogen 7, 12-dimethylbenz[a]anthracene induces a specific po int mutation in Ha-ras gene in this model. In the last few years, several s tudies have shown a correlation between ras activation and alterations in t he expression of cyclin D1 as well as other cell cycle-regulated proteins, but the actual role of these alterations in tumor development had not been determined until a recent study provided genetic and biochemical evidence t hat cyclin D1 is a critical target of oncogenic ras in mouse skin carcinoge nesis. Here we review these results, including the evidence that cyclin D1 has a role as a downstream mediator of ras activity during tumor developmen t. We propose a model in which cyclin D1 has a unique growth-promoting role in tumor development but does not act as an oncogene independently of ras activity. (C) 1999 Wiley-Liss. Inc.