ONCOGENIC ABERRATIONS OF PL6(INK4 CDKN2) AND CYCLIN D1 COOPERATE TO DEREGULATE G(1) CONTROL/

The p16(INK4/CDKN2), D-type cyclins, their partner cyclin-dependent ki nases, and retinoblastoma protein constitute a G(1) regulatory pathway commonly targeted in oncogenesis. We show that, unexpectedly, abnorma lities of p16(INK4/CDKN2) occur concomitantly in two-thirds of cancer cell lines harboring aberrations of cyclin D1. Gene and protein transf er experiments demonstrated that concurrent alterations of cyclin D1 a nd p16 levels cooperate to (de)regulate G(1) control in diploid fibrob lasts, and that both events influence growth of retinoblastoma (RB)-po sitive, but not RB-deficient cancer cells. These results show that bio logical consequences of deregulating individual components along the p athway are unequal, reflecting their hierarchical roles in the G(1) ch eckpoint control. Whereas RB defects eliminate the checkpoint complete ly, aberrations of the upstream components, such as cyclin D1 and p16( INK4/CDKN2), can cooperate in multistep tumorigenesis.