Retinoblastoma-protein-dependent cell-cycle inhibition by the tumour suppressor p16.
D-type cyclins, in association with the cyclin-dependent kinases Cdk4 or Cdk6, promote progression through the G1 phase of the cell cycle by phosphorylating the retinoblastoma protein (RB). The activities of Cdk4 and Cdk6 are constrained by inhibitors such as p16, the product of the CDKN2 gene on human chromosome 9p21 (refs 12-14). The frequent deletion or mutation of CDKN2 in tumour cells suggests that p16 acts as a tumour suppressor. We show that wild-type p16 arrests normal diploid cells in late G1, whereas a tumour-associated mutant of p16 does not. Significantly, the ability of p16 to induce cell-cycle arrest is lost in cells lacking functional RB, including primary fibroblasts from Rb-/- mouse embryos. Thus, loss of p16, overexpression of D-cyclins and loss of RB have similar effects on G1 progression, and may represent a common pathway to tumorigenesis.
Lukas
J
J
Danish Cancer Society, Division of Cancer Biology, Copenhagen.
Parry
D
D
Aagaard
L
L
Mann
D J
DJ
Bartkova
J
J
Strauss
M
M
Peters
G
G
Bartek
J
J
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D002453:Cell Cycle / Q000502:physiology*; D002478:Cells, Cultured; D003001:Cloning, Molecular; D019938:Cyclin D1; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D019941:Cyclin-Dependent Kinase Inhibitor p16; D018844:Cyclin-Dependent Kinases; D016213:Cyclins / Q000502:physiology; D004926:Escherichia coli; D016193:G1 Phase / Q000502:physiology; D016147:Genes, Tumor Suppressor; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008845:Microinjections; D009154:Mutation; D015513:Oncogene Proteins / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000502:physiology*; D014407:Tumor Cells, Cultured
D002352:Carrier Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D016213:Cyclins; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; D016160:Retinoblastoma Protein; D019938:Cyclin D1; D017346:Protein Serine-Threonine Kinases; C495900:CDK4 protein, human; C495911:CDK6 protein, human; C495902:Cdk4 protein, mouse; C495912:Cdk6 protein, mouse; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D018844:Cyclin-Dependent Kinases