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p21^WAF1/CIP1 Mutants Deficient in Inhibiting Cyclin-dependent Kinases (CDKs) Can Promote Assembly of Active Cyclin D/CDK4(6) Complexes in Human Tumor Cells¹

Institute of Cancer Biology, Danish Cancer Society, DK-2100 Copenhagen, Denmark [M. W., J. L., M. S., J. B.]; and Humboldt University, Max Delbrück Center for Molecular Medicine, D-13122 Berlin-Buch, Germany [M. S.]

The cyclin-dependent kinase (CDK) inhibitor p21^WAF1/CIP1 is a multidomain, 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 selectively deficient in binding to either cyclin or CDK are partially impaired 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 suggest a functional subclassification of tumor-specific aberrations of p21. Intriguingly, the subclass exemplified by the melanoma-derived N50S mutant may promote tumorigenesis, by both attenuating CDK-inhibitory function and concomitantly activating the proto-oncogenic cyclin D-dependent kinases.

¹ This work was supported by grants from the Danish Cancer Society, the Danish Medical Research Council (Grant 9600821), and the Human Frontier Science Programme (Grant RG-557/96). M. W. is a Marie Curie fellow, supported by the European Union.

² To whom requests for reprints should be addressed, at Institute of Cancer Biology, Danish Cancer Society, Strandboulevarden 49, DK-2100 Copenhagen, Denmark, Phone: (45) 35 25 73 57; Fax: (45) 35 25 77 21.

Received 8/24/98. Accepted 10/ 1/98.

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