Deregulated Proteolysis of the Cell Cycle Regulator p27Kip1 and Cancers

Reduced expression of p27, a member of CDK inhibitors, is observed in a variety of human cancers, and many studies have indicated that downregulation of the p27 expression correlates with poor prognosis. p27 acts as a negative regulator of the cell cycle, and its degradation by the ubiquitin-proteasome pathway is a critical event for the cell cycle progression to S phase. The degradation of p27 is regulated by phosphorylations prior to ubiquitination that is mediated by the SCF^Skp2 ubiquitin ligase complex. The low levels of p27 protein in many cancer cells seem attributable to enhanced proteolysis. In fact, increased levels of Skp2 protein are found in many tumors, and the overexpression of Skp2 may also be related to the high grade of cancers. Previous reports have suggested that p27 is clinically useful as an independent prognostic marker for cancer patients, and trials of new treatments targeting p27 have already started. p27 is also implicated to play a role in other cell functions, such as cell differentiation, apoptosis, and cell-cell adhesion. Thus, a variety of mechanisms seem to underlie the deregulation of p27 in cancer cells, which remain to be elucidated.