A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4.
The division cycle of eukaryotic cells is regulated by a family of protein kinases known as the cyclin-dependent kinases (CDKs). The sequential activation of individual members of this family and their consequent phosphorylation of critical substrates promotes orderly progression through the cell cycle. The complexes formed by CDK4 and the D-type cyclins have been strongly implicated in the control of cell proliferation during the G1 phase. CDK4 exists, in part, as a multi-protein complex with a D-type cyclin, proliferating cell nuclear antigen and a protein, p21 (refs 7-9). CDK4 associates separately with a protein of M(r) 16K, particularly in cells lacking a functional retinoblastoma protein. Here we report the isolation of a human p16 complementary DNA and demonstrate that p16 binds to CDK4 and inhibits the catalytic activity of the CDK4/cyclin D enzymes. p16 seems to act in a regulatory feedback circuit with CDK4, D-type cyclins and retinoblastoma protein.
Serrano
M
M
Howard Hughes Medical Institute, Cold Spring Harbor Laboratory, New York 11724.
Hannon
G J
GJ
Beach
D
D
D000595:Amino Acid Sequence; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D002453:Cell Cycle; D003001:Cloning, Molecular; D019938:Cyclin D1; D051358:Cyclin-Dependent Kinase 4; D019941:Cyclin-Dependent Kinase Inhibitor p16; D018844:Cyclin-Dependent Kinases; D016213:Cyclins / Q000378:metabolism*; D004247:DNA; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008969:Molecular Sequence Data; D015513:Oncogene Proteins / Q000378:metabolism*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae
D002352:Carrier Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D016213:Cyclins; D015513:Oncogene Proteins; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; D016160:Retinoblastoma Protein; D019938:Cyclin D1; D004247:DNA; D005982:Glutathione Transferase; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases