p12(DOC-1) is a novel cyclin-dependent kinase 2-associated protein.

Regulated cyclin-dependent kinase (CDK) levels and activities are critical for the proper progression of the cell division cycle. p12(DOC-1) is a growth suppressor isolated from normal keratinocytes. We report that p12(DOC-1) associates with CDK2. More specifically, p12(DOC-1) associates with the monomeric nonphosphorylated form of CDK2 (p33CDK2). Ectopic expression of p12(DOC-1) ...
resulted in decreased cellular CDK2 and reduced CDK2-associated kinase activities and was accompanied by a shift in the cell cycle positions of p12(DOC-1) transfectants ( upward arrow G(1) and downward arrow S). The p12(DOC-1)-mediated decrease of CDK2 was prevented if the p12(DOC-1) transfectants were grown in the presence of the proteosome inhibitor clasto-lactacystin beta-lactone, suggesting that p12(DOC-1) may target CDK2 for proteolysis. A CDK2 binding mutant was created and was found to revert p12(DOC-1)-mediated, CDK2-associated cell cycle phenotypes. These data support p12(DOC-1) as a specific CDK2-associated protein that negatively regulates CDK2 activities by sequestering the monomeric pool of CDK2 and/or targets CDK2 for proteolysis, reducing the active pool of CDK2.
Mesh Terms:
Blotting, Western, CDC2-CDC28 Kinases, Cell Cycle, Cell Division, Cell Line, Chromatography, Gel, Cyclin-Dependent Kinase 2, Cyclin-Dependent Kinases, Cysteine Proteinase Inhibitors, Humans, Keratinocytes, Lactones, Lung, Mutagenesis, Site-Directed, Phenotype, Phosphorylation, Protein Binding, Protein Biosynthesis, Protein-Serine-Threonine Kinases, Proteins, Recombinant Fusion Proteins, Time Factors, Tissue Distribution, Transfection, Tumor Suppressor Proteins
Mol. Cell. Biol.
Date: Sep. 01, 2000
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