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Molecular and Cellular Biology, March 2004, p. 2296-2307, Vol. 24, No. 6
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.6.2296-2307.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

SRC Proximal and Core Promoter Elements Dictate TAF1 Dependence and Transcriptional Repression by Histone Deacetylase Inhibitors

Scott M. Dehm,1 Traci L. Hilton,2 Edith H. Wang,2 and Keith Bonham3*

Department of Biochemistry, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5E5,1 Cancer Research Unit, Health Research Division, Saskatchewan Cancer Agency, Saskatoon, Saskatchewan S7N 4H4, Canada,3 Department of Pharmacology, School of Medicine, University of Washington, Seattle, Washington2

Received 8 August 2003/ Returned for modification 1 December 2003/ Accepted 15 December 2003

Histone deacetylase inhibitors (HDIs) induce cell cycle arrest, differentiation, or apoptosis in numerous cancer cell types both in vivo and in vitro. These dramatic effects are the result of a specific reprogramming of gene expression. However, the mechanism by which these agents activate the transcription of some genes, such as p21WAF1, but repress others, such as cyclin D1, is currently unknown. We have been studying the human SRC gene as a model for HDI-mediated transcriptional repression. We found previously that both the tissue-specific and housekeeping SRC promoters were equally repressed by HDIs. Here we show that, despite an overt dissimilarity, both SRC promoters do share similar core promoter elements and transcription is TAF1 dependent. Detailed analysis of the SRC promoters suggested that both core and proximal promoter elements were responsible for HDI-mediated repression. This was confirmed in a series of promoter-swapping experiments with the HDI-inducible, TAF1-independent p21WAF1 promoter. Remarkably, all the SRC-p21WAF1 chimeric promoter constructs were not only repressed by HDIs but also dependent on TAF1. Together these experiments suggest that the overall promoter architecture, rather than discrete response elements, is responsible for HDI-mediated repression, and they implicate core promoter elements in particular as potential mediators of this response.

* Corresponding author. Mailing address: Cancer Research Unit, Health Research Division, Saskatchewan Cancer Agency, 20 Campus Dr., Saskatoon, SK S7N 4H4, Canada. Phone: (306) 655-2315. Fax: (306) 655-2635. E-mail: kbonham{at}scf.sk.ca.

Molecular and Cellular Biology, March 2004, p. 2296-2307, Vol. 24, No. 6
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.6.2296-2307.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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