P21(WAF1 CIP2) MUTANTS DEFICIENT IN INHIBITING CYCLIN-DEPENDENT KINASES (CDKS) CAN PROMOTE ASSEMBLY OF ACTIVE CYCLIN-D CDK4(6) COMPLEXES INHUMAN TUMOR-CELLS/

The cyclin-dependent kinase (CDK) inhibitor p21(WAF1/CIP1) is a multid omain, multifunctional protein and a candidate tumor suppressor, Here, we show that, among rationally designed and tumor-associated mutants of human p21 ectopically expressed in U-2-OS cells, those that are sel ectively deficient in binding to either cyclin or CDK are partially im paired in inhibiting endogenous CDK activities but efficiently promote assembly of active cyclin D/CDK4(6) complexes, These results provide mechanistic insights into the p21-cyclin/CDK interplay in vivo and sug gest a functional subclassification of tumor-specific aberrations of p 21. Intriguingly, the subclass exemplified by the melanoma-derived N50 S mutant may promote tumorigenesis, by both attenuating CDK-inhibitory function and concomitantly activating the proto-oncogenic cyclin D-de pendent kinases.