p27(kip1) expression limits H-Ras-driven transformation and tumorigenesis by both canonical and non-canonical mechanisms

The tumor suppressor protein p27(Kip1) plays a pivotal role in the control of cell growth and metastasis formation. Several studies pointed to different roles for p27(Kip1) in the control of Ras induced transformation, although no explanation has been provided to elucidate these differences. We recently demonstrated that p27(kip1) regulates H-Ras activity via its interaction with stathmin. Here, using in vitro and in vivo models, we show that p27(kip1) is an important regulator of Ras induced transformation. In H-Ras(V12) transformed cells, p27(kip1) suppressed cell proliferation and tumor growth via two distinct mechanisms: 1) inhibition of CDK activity and 2) impairment of MT-destabilizing activity of stathmin. Conversely, in K-Ras4B(V12) transformed cells, p27(kip1) acted mainly in a CDK-dependent but stathmin-independent manner. Using human cancer-derived cell lines and primary breast and sarcoma samples, we confirmed in human models what we observed in mice. Overall, we highlight a pathway, conserved from mouse to human, important in the regulation of H-Ras oncogenic activity that could have therapeutic and diagnostic implication in patients that may benefit from anti-H-Ras therapies.