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CAK-independent Activation of CDK6 by a Viral Cyclin
- Source :
- Molecular Biology of the Cell; December 2001, Vol. 12 Issue: 12 p3987-3999, 13p
- Publication Year :
- 2001
-
Abstract
- In normal cells, activation of cyclin-dependent kinases (cdks) requires binding to a cyclin and phosphorylation by the cdk-activating kinase (CAK). The Kaposi's sarcoma-associated herpesvirus encodes a protein with similarity to D-type cyclins. This KSHV-cyclin activates CDK6, alters its substrate specificity, and renders CDK6 insensitive to inhibition by the cdk inhibitor p16INK4a. Here we investigate the regulation of the CDK6/KSHV-cyclin kinase with the use of purified proteins and a cell-based assay. We find that KSHV-cyclin can activate CDK6 independent of phosphorylation by CAK in vitro. In addition, CAK phosphorylation decreased the p16INK4asensitivity of CDK6/KSHV-cyclin complexes. In cells, expression of CDK6 or to a lesser degree of a nonphosphorylatable CDK6T177Atogether with KSHV-cyclin induced apoptosis, indicating that CDK6 activation by KSHV-cyclin can proceed in the absence of phosphorylation by CAK in vivo. Coexpression of p16 partially protected cells from cell death. p16 and KSHV-cyclin can form a ternary complex with CDK6 that can be detected by binding assays as well as by conformational changes in CDK6. The Kaposi's sarcoma-associated herpesvirus has adopted a clever strategy to render cell cycle progression independent of mitogenic signals, cdk inhibition, or phosphorylation by CAK.
Details
- Language :
- English
- ISSN :
- 10591524 and 19394586
- Volume :
- 12
- Issue :
- 12
- Database :
- Supplemental Index
- Journal :
- Molecular Biology of the Cell
- Publication Type :
- Periodical
- Accession number :
- ejs46607082
- Full Text :
- https://doi.org/10.1091/mbc.12.12.3987