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p12 DOC-1 Is a Novel Cyclin-Dependent Kinase 2-Associated Protein

2000; Taylor & Francis; Volume: 20; Issue: 17 Linguagem: Inglês

10.1128/mcb.20.17.6300-6307.2000

1098-5549

Satoru Shintani, Hiroe Ohyama, Xue Zhang, Jim McBride, Kou Matsuo, Takanori Tsuji, Miaofen G. Hu, Guo‐fu Hu, Yohko Kohno, Michael I. Lerman, Randy Todd, David T. Wong,

Epigenetics and DNA Methylation

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.