CAK-independent activation of CDK6 by a viral cyclin Journal Article
| Authors: | Kaldis, P.; Ojala, P. M.; Tong, L.; Makela, T. P.; Solomon, M. J. |
| Article Title: | CAK-independent activation of CDK6 by a viral cyclin |
| 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 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. |
| Keywords: | retinoblastoma protein; transcription factor tfiih; dependent kinase inhibitor; kaposis-sarcoma; cell-cycle; sarcoma-associated herpesvirus; ring finger protein; catalytic subunit; potential mediator; b-type cyclins |
| Journal Title: | Molecular Biology of the Cell |
| Volume: | 12 |
| Issue: | 12 |
| ISSN: | 1059-1524 |
| Publisher: | The American Society for Cell Biology |
| Date Published: | 2001-12-01 |
| Start Page: | 3987 |
| End Page: | 3999 |
| Language: | English |
| ACCESSION: | WOS:000172701100021 |
| PROVIDER: | wos |
| PUBMED: | 11739795 |
| DOI: | 10.1091/mbc.12.12.3987 |
| PMCID: | PMC60770 |
| Notes: | Article -- Source: Wos |
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