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CAK-independent Activation of CDK6 by a Viral Cyclin

Authors :
Kaldis, Philipp
Ojala, Päivi M.
Tong, Lily
Mäkelä, Tomi P.
Solomon, Mark J.
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