The p27kip1 (p27) tumor suppressor protein is rarely deleted or mutated in human cancers.  Instead, its contribution to transformation is mediated through altered expression or activity due to transcriptional, translational, or post-translational mechanisms.  We previously identified a novel role for p27 binding Growth Factor Receptor-Bound Protein 2 (GRB2) and preventing its association with SOS, a guanine nucleotide exchange factor.  This interaction was observed in MCF10A untransformed breast epithelial cells but was disrupted in MCF7 breast cancer cells.  We found that the overexpression of cyclin D1 and CDK4 in MCF7 cells sequestered phosphorylated p27 and prevented its targeting of GRB2.  Since GRB2-SOS activates the proto-oncogene Ras, the tumor-suppressing function of p27 may involve Ras inhibition. We examined transformed cell lines expressing p27 and observed Ras activity.  We propose that overexpression of cyclin D1 and CDK4 leads to preferential sequestration of p27, ultimately resulting in cellular transformation due to uncontrolled Ras activation.

P27 tumor suppressor protein regulates Ras activity

243rd National Meeting (2012)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.