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Molecular and Cellular Biology, August 2000, p. 5986-5997, Vol. 20, No. 16
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

C/EBPalpha Inhibits Cell Growth via Direct Repression of E2F-DP-Mediated Transcription

Beatrix A. Slomiany,1,2 Kenneth L. D'Arigo,1 Margaret M. Kelly,1,dagger and David T. Kurtz1,2,*

Department of Pharmacology1 and the Environmental Biosciences Program,2 Medical University of South Carolina, Charleston, South Carolina 29425

Received 20 December 1999/Returned for modification 27 January 2000/Accepted 23 May 2000

Using an inducible transcription system which allows the regulated expression of C/EBP isoforms in tissue culture cells, we have found that the ectopic expression of C/EBPalpha , at a level comparable to that found in normal liver tissue, has a pronounced antimitogenic effect in mouse L cells and NIH 3T3 cells. The inhibition of cell division by C/EBPalpha in mouse cells cannot be reversed by simian virus 40 T antigen, by oncogenic ras, or by adenovirus E1a protein. When expressed in thymidine kinase-deficient L cells or 3T3 cells, C/EBPalpha is detected in a protein complex which binds to the E2F binding sites found in the promoters of the genes for E2F-1 and dihydrofolate reductase (DHFR). Bacterially expressed C/EBPalpha has no affinity for these E2F sites, but when recombinant C/EBPalpha is added to nuclear extracts from mouse fibroblasts, a new E2F binding activity appears, which contains the C/EBPalpha protein. Using an E2F-DP1-responsive promoter linked to a reporter gene, it can be shown that C/EBPalpha directly inhibits the induction of this promoter by E2F-DP1 in transient-transfection assays. Furthermore, C/EBPalpha can be shown to inhibit the S-phase induction of the E2F and DHFR promoters in permanent cell lines. These findings delineate a straightforward mechanism for C/EBPalpha -mediated cell growth arrest through repression of E2F-DP-mediated S-phase transcription.

* Corresponding author. Mailing address: Department of Pharmacology, Medical University of South Carolina, Charleston, South Carolina 29425. Phone: (843) 792-5844. Fax: (843) 792-2475. E-mail: kurtzdt{at}musc.edu.

dagger Present address: Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425.

Molecular and Cellular Biology, August 2000, p. 5986-5997, Vol. 20, No. 16
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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