Pinz, Sophia and Unser, Samy and Buob, Dominik and Fischer, Philipp and Jobst, Belinda and Rascle, Anne (2015) Deacetylase inhibitors repress STAT5-mediated transcription by interfering with bromodomain and extra-terminal (BET) protein function. NUCLEIC ACIDS RESEARCH, 43 (7). pp. 3524-3545. ISSN 0305-1048, 1362-4962
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Signal transducer and activator of transcription STAT5 is essential for the regulation of proliferation and survival genes. Its activity is tightly regulated through cytokine signaling and is often upregulated in cancer. We showed previously that the deacetylase inhibitor trichostatin A (TSA) inhibits STAT5-mediated transcription by preventing recruitment of the transcriptional machinery at a step following STAT5 binding to DNA. The mechanism and factors involved in this inhibition remain unknown. We now show that deacetylase inhibitors do not target STAT5 acetylation, as we initially hypothesized. Instead, they induce a rapid increase in global histone acetylation apparently resulting in the delocalization of the bromodomain and extra-terminal (BET) protein Brd2 and of the Brd2-associated factor TBP to hyperacetylated chromatin. Treatment with the BET inhibitor (+)-JQ1 inhibited expression of STAT5 target genes, supporting a role of BET proteins in the regulation of STAT5 activity. Accordingly, chromatin immunoprecipitation demonstrated that Brd2 is associated with the transcriptionally active STAT5 target gene Cis and is displaced upon TSA treatment. Our data therefore indicate that Brd2 is required for the proper recruitment of the transcriptional machinery at STAT5 target genes and that deacetylase inhibitors suppress STAT5-mediated transcription by interfering with Brd2 function.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | PHOSPHORYLATION-ACETYLATION SWITCH; ACUTE LYMPHOBLASTIC-LEUKEMIA; ORDER CHROMATIN-STRUCTURE; DNA-DAMAGE RESPONSE; IN-VIVO; SIGNAL-TRANSDUCTION; TRANSACTIVATION DOMAIN; HISTONE DEACETYLASES; HEMATOPOIETIC-CELLS; MYELOID-LEUKEMIA; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Immunologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 22 Jul 2019 12:14 |
| Last Modified: | 22 Jul 2019 12:14 |
| URI: | https://pred.uni-regensburg.de/id/eprint/5629 |
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