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Vol. 12, Issue 12, 3987-3999, December 2001

CAK-independent Activation of CDK6 by a Viral Cyclin

Philipp Kaldis,^* Päivi M. Ojala,^§ Lily Tong,^¶ Tomi P. Mäkelä,^§ and Mark J. Solomon^*

 ^*Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, Connecticut 06520-8114;  ^§Haartman Institute and Helsinki University Central Hospital, SF-00014 Helsinki, Finland; and  Cellular Biochemistry and Biophysics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021

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 p16^INK4a. 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 p16^INK4a sensitivity of CDK6/KSHV-cyclin complexes. In cells, expression of CDK6 or to a lesser degree of a nonphosphorylatable CDK6^T177A together 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.

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Present addresses: National Cancer Institute, NCI-Frederick, Regulation of Cell Growth Laboratory, Bldg. 560/12-91A, West 7th St., Frederick, MD 21702-1201; ^¶Department of Immunology, Schering-Plough Institute, Kenilworth, NJ 07033.

Corresponding authors. E-mail address: Kaldis{at}ncifcrf.gov and Mark.Solomon{at}yale.edu.

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Molecular Biology of the Cell
Vol. 12, 3987-3999, December 2001
Copyright © 2001 by The American Society for Cell Biology

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