The COOH terminus of p18INK4C distinguishes function from p16INK4A.
The INK4 family of proteins consists of four members which can block progression from the G(1)-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 G(1) 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.
Gump
J
J
Department of Molecular Physiology, University of Vermont, Burlington, VT 05405, USA.
Turner
S
S
Koh
J
J
D000595:Amino Acid Sequence; D001665:Binding Sites; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D002453:Cell Cycle / Q000502:physiology; D018797:Cell Cycle Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000502:physiology*; D050763:Cyclin-Dependent Kinase Inhibitor p18; D004791:Enzyme Inhibitors; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
C493971:CDKN2C protein, human; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18; D004791:Enzyme Inhibitors; D025521:Tumor Suppressor Proteins