Inhibition of ras-induced proliferation and cellular transformation by p16INK4.
The cyclin-dependent kinase 4 (CDK4) regulates progression through the G1 phase of the cell cycle. The activity of CDK4 is controlled by the opposing effects of the D-type cyclin, an activating subunit, and p16INK4, an inhibitory subunit. Ectopic expression of p16INK4 blocked entry into S phase of the cell cycle induced by oncogenic Ha-Ras, and this block was relieved by coexpression of a catalytically inactive CDK4 mutant. Expression of p16INK4 suppressed cellular transformation of primary rat embryo fibroblasts by oncogenic Ha-Ras and Myc, but not by Ha-Ras and E1a. Together, these observations provide direct evidence that p16INK4 can inhibit cell growth.
Serrano
M
M
Howard Hughes Medical Institute, Cold Spring Harbor Laboratory, NY 11724.
Gómez-Lahoz
E
E
DePinho
R A
RA
Beach
D
D
Bar-Sagi
D
D
D017500:Adenovirus E1A Proteins / Q000235:genetics / Q000502:physiology; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D002455:Cell Division; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D051358:Cyclin-Dependent Kinase 4; D019941:Cyclin-Dependent Kinase Inhibitor p16; D018844:Cyclin-Dependent Kinases; D017930:Genes, Reporter; D016161:Genes, Retinoblastoma; D016259:Genes, myc; D011905:Genes, ras; D010957:Plasmids; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D051381:Rats; D016160:Retinoblastoma Protein / Q000502:physiology; D016196:S Phase; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured; D018631:ras Proteins / Q000235:genetics / Q000502:physiology*
D017500:Adenovirus E1A Proteins; D002352:Carrier Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein; D017346:Protein Serine-Threonine Kinases; C495903:Cdk4 protein, rat; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases; D018631:ras Proteins