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Oncogenic Aberrations of p16^INK4/CDKN2 and Cyclin D1 Cooperate to Deregulate G₁ Control¹

Danish Cancer Society, Division of Cancer Biology, Strandboulevarden 49, DK-2100 Copenhagen Ø Denmark [J. L., L. A., M. S., J. B.], and Max-Planck-Gesellschaft, Max-Delbrück-Haus, R. Rössle strasse 10, D-13122, Berlin-Buch, Germany [M. S.]

The p16^INK4/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 p16^INK4/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 p16^INK4/CDKN2, can cooperate in multistep tumorigenesis.

¹ This work was supported by grants from the Danish Cancer Society.

² To whom requests for reprints should be addressed.

Received 9/ 6/95. Accepted 9/20/95.

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