This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ohta, T. Articles by Xiong, Y. Search for Related Content PubMed PubMed Citation Articles by Ohta, T. Articles by Xiong, Y.

T-Loop Deletion of CDC2 from Breast Cancer Tissues Eliminates Binding to Cyclin B1 and Cyclin-dependent Kinase Inhibitor p21¹

First Department of Surgery [T. O., M. F., S. Y.] and Department of Biochemistry [K. O., F. I.], St. Marianna University School of Medicine, Kawasaki 216, Japan; Department of Biotechnology, School of Science and Engineering, Ishinomaki Senshu University, Ishinomaki 986-80, Japan [K. S.]; and Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599 [T. O., Y. X.]

The eukaryotic cell cycle is regulated by a highly conserved family of protein kinases, the cyclin-dependent kinases (CDKs). Monomeric free CDKs do not possess enzymatic activity, largely due to the steric hindrance caused by the T-loop at the entrance of the catalytic cleft, making ATP inaccessible to the substrate. Binding of a cyclin, primarily to the NH²-terminal lobe of the CDK that surrounds the PSTAIRE helix, induces a large conformational change in the PSTAIRE helix of the CDK and also causes the T-loop to move out of the way of the catalytic cleft. We identified from breast cancer tissues a novel variant of human CDC2, termed CDC2T, that lacks 171 nucleotides corresponding to 57 amino acids, which compose most of the T-loop. CDC2T was detected in 10 of 14 breast cancer tissues analyzed, whereas it was not detectable in diploid human fibroblast cell lines or in interleukin 2-stimulated normal human lymphocytes. CDC2T protein is unable to complex with cyclin B1 and lacks histone H1 kinase activity. CDC2T also fails to bind to the CDK inhibitor p21. These results indicate that the T-loop not only plays a key role in keeping a free CDK in its inactive state but also in facilitating CDK activation by promoting cyclin binding.

¹ This study was supported by a Grant-in-Aid for General Scientific Research from the Ministry of Education, Science, Sports and Culture of Japan and by a United States Public Health Service Grant CA-65572 from the NIH (to Y. X.).

² To whom requests for reprints should be addressed, at 22-068 Lineberger Building, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599. Phone: (919) 962-2138; Fax: (919) 966-8799; E-mail: tomo@imap.unc.edu.

Received 6/27/97. Accepted 1/23/98.

This article has been cited by other articles:

				R. Hayami, K. Sato, W. Wu, T. Nishikawa, J. Hiroi, R. Ohtani-Kaneko, M. Fukuda, and T. Ohta Down-regulation of BRCA1-BARD1 Ubiquitin Ligase by CDK2 Cancer Res., January 1, 2005; 65(1): 6 - 10. [Abstract] [Full Text] [PDF]

				B. F. Hinnebusch, S. Meng, J. T. Wu, S. Y. Archer, and R. A. Hodin The Effects of Short-Chain Fatty Acids on Human Colon Cancer Cell Phenotype Are Associated with Histone Hyperacetylation J. Nutr., May 1, 2002; 132(5): 1012 - 1017. [Abstract] [Full Text] [PDF]