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

STAT5是转录的信号转导和激活因子，是细胞因子信号传导的重要下游效应因子。它在调节免疫应答、细胞增殖、分化、生存和肿瘤发生等方面发挥着关键作用。STAT5激活转录的机制才刚刚开始被揭示。我们最近表明，转录机制的组装和STAT5的转录激活需要脱乙酰酶活性（Rascle et al. 2003）。我们还证明，这种去乙酰化酶活性并不针对组蛋白乙酰化或染色质重塑（Rascle等人，2003；Rascle和Lees， 2003），因此表明它针对STAT5转录起始所需的非组蛋白。去乙酰化酶及其底物代表了STAT5驱动的恶性肿瘤治疗干预的潜在靶点，因此它们的鉴定不仅对更好地理解STAT5信号传导，而且在临床领域具有广泛的意义。因此，我们项目的主要目标是：1。鉴定参与stat5介导的转录的去乙酰化酶；鉴定乙酰化底物，其去乙酰化是招募转录机制和STAT5反激活所必需的。

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.