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Molecular and Cellular Biology, June 2003, p. 4162-4173, Vol. 23, No. 12
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.12.4162-4173.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Deacetylase Activity Is Required for Recruitment of the Basal Transcription Machinery and Transactivation by STAT5

Anne Rascle,* James A. Johnston,{dagger} and Bruno Amati{ddagger}

Department of Discovery Research, DNAX Research Inc., Palo Alto, California 94304

Received 13 December 2002/ Returned for modification 4 February 2003/ Accepted 31 March 2003

The signal transducer and activator of transcription STAT5 plays a major role in the cellular response to cytokines, but the mechanism by which it activates transcription remains poorly understood. We show here that deacetylase inhibitors (trichostatin A, suberoylanilide hydroxamic acid, and sodium butyrate) prevent induction of endogenous STAT5 target genes, implying that a deacetylase activity is required for that process. Microarray analyses revealed that this requirement is common to all STAT5 target genes. Using chromatin immunoprecipitation, we show that, following STAT5 DNA binding, deacetylase inhibitors block transcription initiation by preventing recruitment of the basal transcription machinery. This inhibition is not due to effects on histone H3 and H4 acetylation or chromatin remodeling within the promoter region. This novel mechanism of transactivation by STAT5 provides a rationale for the use of deacetylase inhibitors for therapeutic intervention in STAT5-associated cancers.

* Corresponding author. Mailing address: Department of Discovery Research, DNAX Research Inc., Palo Alto, CA 94304. Phone: (650) 496-6532. Fax: (650) 496-1200. E-mail: anne.rascle{at}dnax.org.

{dagger} Present address: Department of Microbiology and Immunology, Queen's University, Belfast BT9 7BL, Northern Ireland.

{ddagger} Present address: European Institute of Oncology, 20141 Milan, Italy.

Molecular and Cellular Biology, June 2003, p. 4162-4173, Vol. 23, No. 12
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.12.4162-4173.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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