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CAK-independent activation of CDK6 by a viral cyclin

Kaldis, P. LU orcid ; Ojala, P. M. ; Tong, L. ; Mäkelä, T. P. and Solomon, M. J. (2001) In Molecular Biology of the Cell 12(12). p.3987-3999
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 p16INK4a sensitivity of CDK6/KSHV-cyclin complexes. In cells, expression of... (More)

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 p16INK4a sensitivity of CDK6/KSHV-cyclin complexes. In cells, expression of CDK6 or to a lesser degree of a nonphosphorylatable CDK6T177A 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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author
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publishing date
type
Contribution to journal
publication status
published
subject
in
Molecular Biology of the Cell
volume
12
issue
12
pages
13 pages
publisher
American Society for Cell Biology
external identifiers
  • pmid:11739795
  • scopus:0035665341
ISSN
1059-1524
DOI
10.1091/mbc.12.12.3987
language
English
LU publication?
no
id
a551f099-40a6-4123-8394-1630b77e4726
date added to LUP
2019-09-18 14:30:38
date last changed
2024-01-01 20:44:27
@article{a551f099-40a6-4123-8394-1630b77e4726,
  abstract     = {{<p>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<sup>INK4a</sup>. 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<sup>INK4a</sup> sensitivity of CDK6/KSHV-cyclin complexes. In cells, expression of CDK6 or to a lesser degree of a nonphosphorylatable CDK6<sup>T177A</sup> 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.</p>}},
  author       = {{Kaldis, P. and Ojala, P. M. and Tong, L. and Mäkelä, T. P. and Solomon, M. J.}},
  issn         = {{1059-1524}},
  language     = {{eng}},
  month        = {{01}},
  number       = {{12}},
  pages        = {{3987--3999}},
  publisher    = {{American Society for Cell Biology}},
  series       = {{Molecular Biology of the Cell}},
  title        = {{CAK-independent activation of CDK6 by a viral cyclin}},
  url          = {{http://dx.doi.org/10.1091/mbc.12.12.3987}},
  doi          = {{10.1091/mbc.12.12.3987}},
  volume       = {{12}},
  year         = {{2001}},
}