Induction of cyclin D1 overexpression by activated ras

Activated ras genes are known to alter control of cell proliferation. This is consistent with the fact that ras proteins are a key component of the biochemical pathway triggered by ligand-bound cell surface receptors that are tyrosine kinases. Although an important part of the ras signaling pathway has been recently uncovered, the molecular target(s) that mediates the effects of ras on cell cycle control remains unknown. Cyclins and cyclin-dependent kinases are key molecules in the control of cell cycle. Cyclin D1, in particular, is a critical target for proliferative signals in G1 and it has been shown that ectopic overexpression of this cyclin can significantly alter cell cycle regulation. Here we report that activated ras induces significant overexpression of cyclin D1 in epithelial cells derived from normal rat intestine and mouse mammary gland. A definitive causal role for activated ras in this overexpression is demonstrated by using intestinal cells transfected with an inducible ras expression vector. Treatment of the ras-transformed intestinal clones with anti-sense cyclin D1 oligonucleotides reduces their rate of cell proliferation indicating that the increment in cyclin D1 expression induced by activated ras is instrumental in the higher rate of cell proliferation conferred by the ras oncogene to the IEC cells. Based on these results we propose that, at least in certain cell types, cyclin D1 can be one of the mediators of the transforming action of activated ras.