Role of the Cdk Inhibitor Sic 1 in Start

Nearly 180,000 women will develop breast cancer in 1999 and 44,000 will die. Cancer is essentially a disease of inappropriate proliferation due to a loss of normal cell cycle controls. We study cell cycle controls in the budding yeast S. cerevisiae. We have shown that the formation of active G1-cyclin dependent kinase complexes Cdks is rate limiting for cell cycle progression. The activity of these complexes is regulated through their association with highly unstable G1 cyclins. G1 cyclins are constitutively unstable, and their only essential function is to phosphorylate the B-type Cdk inhibitor, Sic1, and target it for degradation. Sic1 is one of few known in vivo substrates of yeast G1-Cdks. The amount and phosphorylation state of Sic1 appears to determine the timing and size of cell division. Sic1 mutants lacking several phosphorylation sites are stabilized and completely block cell cycle progression. Thus, the phosphorylation and subsequent degradation of Sic1 appears to be the critical step in commitment to cell cycle progression. By studying the mechanism of cell cycle control, we can begin to understand how cell cycle defects leads to abnormal proliferation, and how by preventing inappropriate proliferation, we may be able to reduce the incidence of breast cancers.