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Molecular and Cellular Biology, September 2000, p. 6300-6307, Vol. 20, No. 17
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

p12DOC-1 Is a Novel Cyclin-Dependent Kinase 2-Associated Protein

Satoru Shintani,1 Hiroe Ohyama,1 Xue Zhang,1,2 Jim McBride,1 Kou Matsuo,1 Takanori Tsuji,1 Miaofen G. Hu,1 Guofu Hu,3 Yohko Kohno,1 Michael Lerman,4 Randy Todd,5 and David T. W. Wong1,*

Laboratory of Molecular Pathology1 and Laboratory of Oral and Maxillofacial Surgery,5 School of Dental Medicine, and Center for Biochemical and Biophysical Sciences and Medicine, Medical School,3 Harvard University, Boston, Massachusetts 02115; Department of Cell Biology, China Medical University, Shenyang, People's Republic of China2; and Intramural Research Support Program, SAIC Frederick, and Laboratory of Immunobiology, DBS, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, Maryland 217024

Received 15 December 1999/Returned for modification 8 February 2000/Accepted 15 June 2000

Regulated cyclin-dependent kinase (CDK) levels and activities are critical for the proper progression of the cell division cycle. p12DOC-1 is a growth suppressor isolated from normal keratinocytes. We report that p12DOC-1 associates with CDK2. More specifically, p12DOC-1 associates with the monomeric nonphosphorylated form of CDK2 (p33CDK2). Ectopic expression of p12DOC-1 resulted in decreased cellular CDK2 and reduced CDK2-associated kinase activities and was accompanied by a shift in the cell cycle positions of p12DOC-1 transfectants (up-arrow  G1 and down-arrow  S). The p12DOC-1-mediated decrease of CDK2 was prevented if the p12DOC-1 transfectants were grown in the presence of the proteosome inhibitor clasto-lactacystin beta -lactone, suggesting that p12DOC-1 may target CDK2 for proteolysis. A CDK2 binding mutant was created and was found to revert p12DOC-1-mediated, CDK2-associated cell cycle phenotypes. These data support p12DOC-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.

* Corresponding author. Mailing address: Harvard University, School of Dental Medicine, 188 Longwood Ave., Boston, MA 02115. Phone: (617) 432-1834. Fax: (617) 432-2449. E-mail: David_Wong{at}hms.med.harvard.edu.

Molecular and Cellular Biology, September 2000, p. 6300-6307, Vol. 20, No. 17
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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