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The COOH Terminus of p18INK4C Distinguishes Function from p16INK4A¹

Departments of Molecular Physiology and Biophysics [J. G.], Pathology [S. T., J. K.], and Medicine [J. K.], University of Vermont, Burlington, Vermont 05405

The INK4 family of proteins consists of four members which can block progression from the G₁-to-S phase of the cell cycle by inhibiting the activity of cyclin dependent kinases (cdks) 4 and 6. Although the gene encoding p16^INK4a is commonly inactivated in human tumors, p18^INK4c is rarely altered. We show here that overexpression of p18^INK4c does not block cell cycle progression in a T-cell acute lymphocytic leukemia cell line (CEM) sensitive to p16^INK4a-mediated G₁ arrest. A chimera consisting of the kinase-binding region of p16^INK4a fused to the COOH terminus of p18^INK4c is active in all known biochemical assays for INK4 function, but it does not arrest CEM cells. These data imply a novel level of p18^INK4c regulation mediated through the COOH terminus and suggest that functional differences might underlie the distinct mutational profiles observed for p16^INK4a and p18^INK4c in tumors.