Transcriptional regualtion by the oncoprotein STAT5: role of acetylation/deacetylation and implications for STAT5-associated cancers

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The signal transducer and activator of transcription STAT5 functions as an important downstream effector of cytokine signaling. It plays key roles in regulating immune responses, cell proliferation, differentiation, survival and oncogenesis. The mechanism by which STAT5 activates transcription is only starting to be unraveled. We have recently shown that a deacetylase activity is required for assembly of the transcriptional machinery and transcriptional activation by STAT5 (Rascle et al. 2003). We also demonstrated that this deacetylase activity is not targeting histone acetylation or chromatin remodeling (Rascle et al., 2003; Rascle and Lees, 2003), hence suggesting that it is targeting a non-histone protein required for transcriptional initiation by STAT5. The deacetylase and its substrate(s) represent potential targets for therapeutic intervention in STAT5-driven malignancies, and their identification has thus wide implications not only for a better understanding of STAT5 signaling but also in the clinical field. Accordingly, the main goals of our project are to: 1. identify the deacetylase involved in STAT5-mediated transcription, 2. identify the acetylated substrate, whose deacetylation is required for recruitment of the transcriptional machinery and transactivation by STAT5.