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PMID: 10075928 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

The p21(Cip1) and p27(Kip1) CDK 'inhibitors' are essential activators of cyclin D-dependent kinases in murine fibroblasts.

The EMBO journal ·Vol. 18 ·No. 6 ·1999-03-15 ·Pages 1571-83

Cheng M, Olivier P, Diehl JA, Fero M, Roussel MF, Roberts JM, Sherr CJ

Abstract

The widely prevailing view that the cyclin-dependent kinase inhibitors (CKIs) are solely negative regulators of cyclin-dependent kinases (CDKs) is challenged here by observations that normal up-regulation of cyclin D- CDK4 in mitogen-stimulated fibroblasts depends redundantly upon p21(Cip1) and p27(Kip1). Primary mouse embryonic fibroblasts that lack genes encoding both p21 and p27 fail to assemble detectable amounts of cyclin D-CDK complexes, express cyclin D proteins at much reduced levels, and are unable to efficiently direct cyclin D proteins to the cell nucleus. Restoration of CKI function reverses all three defects and thereby restores cyclin D activity to normal physiological levels. In the absence of both CKIs, the severe reduction in cyclin D-dependent kinase activity was well tolerated and had no overt effects on the cell cycle.

MeSH Terms
Animals Cell Cycle Proteins Cell Line Cells, Cultured Cyclin D Cyclin-Dependent Kinase 4 Cyclin-Dependent Kinase Inhibitor p21 Cyclin-Dependent Kinase Inhibitor p27 Cyclin-Dependent Kinases/antagonists & inhibitors,metabolism Cyclins/deficiency,metabolism Embryo, Mammalian Enzyme Inhibitors/metabolism Fibroblasts/cytology,physiology Humans Kinetics Mice Mice, Knockout Microtubule-Associated Proteins/deficiency,metabolism Proto-Oncogene Proteins Recombinant Fusion Proteins/metabolism Transfection Tumor Suppressor Proteins
Chemicals
CDKN1A protein, human Cdkn1a protein, mouse Cdkn1b protein, mouse Cell Cycle Proteins Cyclin D Cyclin-Dependent Kinase Inhibitor p21 Cyclins Enzyme Inhibitors Microtubule-Associated Proteins Proto-Oncogene Proteins Recombinant Fusion Proteins Tumor Suppressor Proteins Cyclin-Dependent Kinase Inhibitor p27 CDK4 protein, human Cdk4 protein, mouse Cyclin-Dependent Kinase 4 Cyclin-Dependent Kinases
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Cheng M
Department of Tumor Cell Biology, St Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38105, USA.
Olivier P
Diehl J A
Fero M
Roussel M F
Roberts J M
Sherr C J
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Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
DOI
10.1093/emboj/18.6.1571
Published
1999-03-15
Pages
1571-83
Language
English
Region
England
NLM ID
8208664
PMCID
PMC1171245
Subset
IM
Grants
NCI NIH HHS · CA-21765 · United States
NCI NIH HHS · CA-56819 · United States
NCI NIH HHS · T32-CA-70089 · United States
External Links
PubMed source DOI: 10.1093/emboj/18.6.1571 PMC Full Text View journal details
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