Document Detail

Why minimal is not optimal: driving the mammalian cell cycle--and drug discovery--with a physiologic CDK control network.
MedLine Citation:
PMID:  22732498     Owner:  NLM     Status:  MEDLINE    
Progression through the eukaryotic cell division cycle is governed by the activity of cyclin-dependent kinases (CDKs). For a CDK to become active it must (1) bind a positive regulatory subunit (cyclin) and (2) be phosphorylated on its activation (T) loop. In metazoans, multiple CDK catalytic subunits, each with a distinct set of preferred cyclin partners, regulate the cell cycle, but it has been difficult to assign functions to individual CDKs in vivo. Biochemical analyses and experiments with dominant-negative alleles suggested that specific CDK/cyclin complexes regulate different events, but genetic loss of interphase CDKs (Cdk2, -4 and -6), alone or in combination, did not block proliferation of cells in culture. These knockout and knockdown studies suggested redundancy or plasticity built into the CDK network but did not address whether there was true redundancy in normal cells with a full complement of CDKs. Here, we discuss recent work that took a chemical-genetic approach to reveal that the activity of a genetically non-essential CDK, Cdk2, is required for cell proliferation when normal cyclin pairing is maintained. These results have implications for the systems-level organization of the cell cycle, for regulation of the restriction point and G 1/S transition and for efforts to target Cdk2 therapeutically in human cancers.
Karl A Merrick; Robert P Fisher
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2012-07-15
Journal Detail:
Title:  Cell cycle (Georgetown, Tex.)     Volume:  11     ISSN:  1551-4005     ISO Abbreviation:  Cell Cycle     Publication Date:  2012 Jul 
Date Detail:
Created Date:  2012-07-25     Completed Date:  2012-11-26     Revised Date:  2013-07-16    
Medline Journal Info:
Nlm Unique ID:  101137841     Medline TA:  Cell Cycle     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2600-5     Citation Subset:  IM    
Department of Structural and Chemical Biology, Mount Sinai School of Medicine, New York, NY, USA.
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MeSH Terms
Cyclin-Dependent Kinase 2 / metabolism
Cyclin-Dependent Kinases / antagonists & inhibitors,  metabolism*
Cyclins / metabolism
Drug Evaluation, Preclinical
G1 Phase
Gene Targeting
HCT116 Cells
S Phase
Grant Support
Reg. No./Substance:
0/Cyclins; EC Kinase 2; EC Kinases

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