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Originally published In Press as doi:10.1074/jbc.M011587200 on May 21, 2001

J. Biol. Chem., Vol. 276, Issue 31, 29200-29209, August 3, 2001
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CCAAT/Enhancer-binding Protein-alpha Cooperates with p21 to Inhibit Cyclin-dependent Kinase-2 Activity and Induces Growth Arrest Independent of DNA Binding*

Thurl E. HarrisDagger §, Jeffrey H. Albrecht, Makoto Nakanishi||, and Gretchen J. Darlington§**

From the Dagger  Cell and Molecular Biology Program and the § Roy M. and Phyllis Gough Huffington Center on Aging, Baylor College of Medicine, Houston, Texas 77030, the  Department of Medicine, Hennepin County Medical Center, Minneapolis, Minnesota 55415, and the || Department of Biochemistry, Nagoya City University Medical School, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan

CCAAT/enhancer-binding protein-alpha (C/EBPalpha ) is a basic leucine zipper protein that controls transcription of genes important for liver function, white adipose tissue development, and granulocyte differentiation. In addition to its function in controlling gene expression in differentiated tissues, C/EBPalpha is also associated with an antimitotic activity. We have previously demonstrated that C/EBPalpha interacts with p21, a cyclin-dependent kinase (CDK) inhibitor, and that C/EBPalpha inhibits proliferation when expressed in several different cell types (Timchenko, N. A., Harris, T. E., Wilde, M., Bilyeu, T. A., Burgess-Beusse, B. L., Finegold, M. J., and Darlington, G. J. (1997) Mol. Cell. Biol. 17, 7353-7361). Here we define the regions of C/EBPalpha required for interaction with p21 and demonstrate that CDK2 also interacts with C/EBPalpha . We show that C/EBPalpha can cooperate with p21 to inhibit CDK2 activity in vitro. The effect of C/EBPalpha on CDK2 activity requires the p21 and CDK2 interaction sites within C/EBPalpha . C/EBPalpha mutants incapable of inhibiting CDK2 activity in vitro do not inhibit proliferation in cultured cells. However, C/EBPalpha mutants defective in DNA binding inhibit proliferation as effectively as the wild-type protein. These findings show that C/EBPalpha -mediated growth arrest occurs through protein interactions and is independent of its transcriptional activity.

* This work was supported by National Institutes of Health Grants T32 AG-00183 (to T. E. H.), AG-13663 (to G. J. D.), and DK-54921 (to J. H. A.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

** To whom correspondence should be addressed: Roy M. and Phyllis Gough Huffington Center on Aging, Rm. N810, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. Tel.: 713-798-1565; Fax: 713-798-4161; E-mail: gretchen@bcm.tmc.edu.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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