Oncogenic aberrations of p16INK4/CDKN2 and cyclin D1 cooperate to deregulate G1 control.
The p16INK4/CDKN2, D-type cyclins, their partner cyclin-dependent kinases, and retinoblastoma protein constitute a G1 regulatory pathway commonly targeted in oncogenesis. We show that, unexpectedly, abnormalities of p16INK4/CDKN2 occur concomitantly in two-thirds of cancer cell lines harboring aberrations of cyclin D1. Gene and protein transfer experiments demonstrated that concurrent alterations of cyclin D1 and p16 levels cooperate to (de)regulate G1 control in diploid fibroblasts, and that both events influence growth of retinoblastoma (RB)-positive, but not RB-deficient cancer cells. These results show that biological consequences of deregulating individual components along the pathway are unequal, reflecting their hierarchical roles in the G1 checkpoint control. Whereas RB defects eliminate the checkpoint completely, aberrations of the upstream components, such as cyclin D1 and p16INK4/CDKN2, can cooperate in multistep tumorigenesis.
Lukas
J
J
Danish Cancer Society, Division of Cancer Biology, Copenhagen O, Denmark.
Aagaard
L
L
Strauss
M
M
Bartek
J
J
D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D002455:Cell Division / Q000502:physiology; D002869:Chromosome Aberrations; D019938:Cyclin D1; D019941:Cyclin-Dependent Kinase Inhibitor p16; D016213:Cyclins / Q000235:genetics / Q000502:physiology*; D016193:G1 Phase / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology*; D015513:Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D014407:Tumor Cells, Cultured
D002352:Carrier Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D016213:Cyclins; D015513:Oncogene Proteins; D019938:Cyclin D1