Both p16 and p21 Families of Cyclin-dependent Kinase (CDK) Inhibitors Block the Phosphorylation of Cyclin-dependent Kinases by the CDK-activating Kinase (*)
- From the (1) Departments of Medicine and
- (2) Biochemistry and Biophysics, the
- (3) Curriculum in Genetics and Molecular Biology, and the
- (4) Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599-7295
- § Leukemia Society Scholar. To whom correspondence should be addressed: CB 7295, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599. Tel.: 919-966-1352; Fax: 919-966-3015; medetl{at}med.unc.edu
Abstract
Phosphorylation of cyclin-dependent kinases (CDKs) by the CDK-activating kinase is required for the activation of CDK enzymes.
Members of two families of CDK inhibitors, p16/p18 and p21/p27, become physically associated with and inhibit the activity
of CDKs in response to a variety of growth-modulating signals. Here, we show that the representative members of both families
of CDK inhibitors, p21
, p27
, and p18, can prevent the phosphorylation of their CDK partners, CDK2 and CDK6, by CDK-activating kinase. No direct interaction
between CDK-activating kinase and the CDK inhibitors could be detected, suggesting that binding of these CDK inhibitors to
CDK subunits renders CDK inaccessible to the CDK-activating kinase phosphorylation. These findings suggest that a general
mechanism of CDK inhibitor function is to block the phosphorylation of CDK enzymes by CDK-activating kinase.
Footnotes
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↵* This work was supported by Grant P50-CA-58223 from the National Institutes of Health, NCI (SPORE in breast cancer, to E. T. L., Y. X., and O. A.), and start-up funds from the University of North Carolina at Chapel Hill (to Y. X.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore by hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵1 The abbreviations used are:
- CDK
-
cyclin-dependent kinase
- CAK
-
CDK-activating kinase
- PCR
-
polymerase chain reaction
- GST
-
glutathione S-transferase.
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↵2K. L. Guan, C. W. Jenkins, Y. Li, M. Zariwala, S. Noh, X. Wu, and Y. Xiong, submitted for publication.
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↵3D. R. Mayrose, M. A. Nichols, Y. Xiong, and H. Ke, submitted for publication.
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- Received April 5, 1995.
- Revision received May 5, 1995.
- © 1995 by The American Society for Biochemistry and Molecular Biology, Inc.
