The tumor suppresser P27kip1 (p27) inhibits cyclin dependent kinases (CDKs). Previous work indicated CDKs can phosphorylate p27 and target it for degradation, suggesting p27 negatively regulates other cellular targets. Growth factor receptor-bound protein 2 (GRB2) was identified as a novel p27 binding partner. GRB2 helps transmit proliferative signals via the Ras/Map Kinase pathway. Thus, p27 tumor suppressing function could involve negative regulation of Ras, a well known proto-oncogene.  Previous work showed p27 association with GRB2 prevents interaction with SOS, a guanine nucleotide exchange factor that activates Ras. We have now investigated disruption of this novel pathway in breast cancer cells. P27 targets GRB2 in normal breast epithelial cells, and this pathway is deregulated in breast cancer cells. The mechanism involves over expressed cyclin D, which binds and sequesters p27. These results provide a new hypothesis for why p27 is so often disrupted in many types of aggressive human cancers.

Novel role for the tumor suppressor p27Kip1 in cancer

243rd National Meeting (2012)

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