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p21WAF1/CIP1 mutants deficient in inhibiting cyclin-dependent kinases (CDKs) can promote assembly of active cyclin D/CDK4(6) complexes in human tumor cells1

Item Type:Article
Title:p21WAF1/CIP1 mutants deficient in inhibiting cyclin-dependent kinases (CDKs) can promote assembly of active cyclin D/CDK4(6) complexes in human tumor cells1
Creators Name:Welcker, M. and Lukas, J. and Strauss, M. and Bartek, J.
Abstract:The cyclin-dependent kinase (CDK) inhibitor p21WAF1/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.
Keywords:Cyclins, Tumor Suppressor Genes, Melanoma, Neoplasm Proteins, Point Mutation, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins, Cultured Tumor Cells
Source:Cancer Research
ISSN:0008-5472
Publisher:American Association for Cancer Research (U.S.A.)
Volume:58
Number:22
Page Range:5053-5056
Date:15 November 1998
Official Publication:http://cancerres.aacrjournals.org/content/58/22/5053.abstract
PubMed:View item in PubMed

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