Oncogenic aberrations of p16INK4/CDKN2 and cyclin D1 cooperate to deregulate G1 control
Lukas, J.; Aagaard, L.; Strauss, M.; Bartek, J.
Cancer Research 55(21): 4818-4823
1995
ISSN/ISBN: 0008-5472 PMID: 7585513 Document Number: 453261
The p16-INK4/CDKN2, D-type cyclins, their partner cyclin-dependent kinases, and retinoblastoma protein constitute a G, regulatory pathway commonly targeted in oncogenesis. We show that, unexpectedly, abnormalities of p16-INK/4CDKN2 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 deregulate G-1 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 G-1 checkpoint control. Whereas RB defects eliminate the checkpoint completely, aberrations of the upstream components, such as cyclin D1 and p16-INK4/CDKN2, can cooperate in multistep tumorigenesis.