MAP kinase cascade is required for p27 downregulation and S phase entry in fibroblasts and epithelial cells

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Abstract
The present report delineates the critical pathway in the G1 phase involved in downregulation of p27Kip1, a cyclin-dependent kinase inhibitor, which plays a pivotal role in controlling entry into the S phase of the cell cycle. In resting CCL39 fibroblasts and IEC-6 intestinal epithelial cells, protein levels of p27Kip1 were elevated but dramatically decreased on serum stimulation, along with hyperphosphorylation of pRb and increased CDK2 activity. In both cell types, expression of ras resulted in an increase of basal and serum-stimulated E2F-dependent transcriptional activity and a reduction in p27Kip1 protein levels as well. The role of the mitogen-activated protein (MAP) kinase cascade in p27Kip1 reduction and S phase reentry was reinforced by the blockades of serum-induced E2F-dependent transcriptional activity and p27Kip1 downregulation with the MKK-1/2 inhibitor PD-98059. In both cell lines, downregulation of p27Kip1 was associated with a repression of its synthesis, an event mediated by the p42/p44 MAP kinase pathway. Using an antisense approach, we demonstrated that p27Kip1 may control cell cycle exit in both cell types. These data indicate that activation of the MAP kinase cascade is required for S phase entry and p27Kip1 downregulation in fibroblasts and epithelial cells.