Deacetylase inhibitors repress STAT5-mediated transcription by interfering with bromodomain and extra-terminal (BET) protein function.
Bottom Line: 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.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.
Affiliation: Stat5 Signaling Research Group, Institute of Immunology, University of Regensburg, 93053 Regensburg, Germany.Show MeSH
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Mentions: One candidate for a chromatin-associated factor interacting with both acetylated histones and the transcriptional machinery (TBP, RNA polymerase II) is Brd2, which was recently implicated in the regulation of STAT5 activity in leukemia cell lines (42). Brd2 belongs to the BET proteins. The mammalian BET family comprises beside Brd2 the Brd3, Brd4 and BrdT proteins. BET family proteins are transcriptional regulators containing a double bromodomain at their amino-terminus and an extra-terminal protein–protein interaction domain in their carboxy-terminal region (80). They bind to acetylated histones and regulate transcription through interactions with transcription factors, multiple chromatin-modifying enzymes and components of the transcriptional machinery such as TBP and RNA polymerase II (80–86). In support to a role of Brd2 in STAT5-dependent transcriptional regulation in Ba/F3 cells, expression of the STAT5 target genes Cis, Osm and c-Myc in response to IL-3 was inhibited by the BET-specific inhibitor (+)-JQ1 (thereafter referred to as JQ1) in a dose-dependent manner (Figure 9). In contrast, expression of the control genes c-Fos, p21 and 36b4 was either increased or remained unaffected (Figure 9). However, no cooperative effect between JQ1 and TSA was found in the presence of sub-optimal concentrations of both compounds (Figure 9), suggesting that both compounds exert partially overlapping effects.
Affiliation: Stat5 Signaling Research Group, Institute of Immunology, University of Regensburg, 93053 Regensburg, Germany.