CAK-independent activation of CDK6 by a viral cyclin
(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.
(Less)
- author
- Kaldis, P. LU ; Ojala, P. M. ; Tong, L. ; Mäkelä, T. P. and Solomon, M. J.
- publishing date
- 2001-01-01
- 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
-
- scopus:0035665341
- pmid:11739795
- 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}}, }