P27Kip1 Tumor Suppressor and Multi-Step Tumorigenesis.

摘要

Mutations in genes that regulate the cell cycle are the most common genetic changes in cancer cells. P27kipl is a member of the Cip/Kip family of cyclin-dependent kinase inhibitors. Decreased p27 expression is found in a wide variety of human neoplasms and is associated with poor patient outcome in many human cancers. Although these studies of p27 expression in primary tumors have correlated low p27 expression with poor prognosis, they do not demonstrate that p27 loss is a causal step in tumorigenesis. In mice however, p27 functions as a tumor suppressor that exhibits haplo- insufficiency. The goal of this research was to investigate the role of p27 in tumorigenesis by characterizing mechanisms of p27-associated tumorigenesis, and identifying proteins that cooperate with p27-loss during tumorigenesis. Using insertional mutagenesis, we identified several novel and previously known oncogenes that cooperate with p27-loss during lymphomagenesis. We also examined the interaction of p27-loss with mutations within the Wnt pathway in mice, but failed to observe synergy during mammary carcinogenesis. Finally, we specifically investigated the hypothesis that p27 and p130, a member of the Retinoblastoma protein family, cooperate in tumor suppression. However, our studies did not reveal cooperativity between these two proteins with respect to tumorigenesis.