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首页> 外文期刊>Molecular and Cellular Biology >Acetylation-Mediated Transcriptional Activation of the ETS Protein ER81 by p300, P/CAF, and HER2/Neu
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Acetylation-Mediated Transcriptional Activation of the ETS Protein ER81 by p300, P/CAF, and HER2/Neu

机译：乙酰化介导的p300，P / CAF和HER2 / Neu对ETS蛋白ER81的转录激活

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摘要

The regulated expression of the ETS transcription factor ER81 is a prerequisite for normal development, and its dysregulation contributes to neoplasia. Here, we demonstrate that ER81 is acetylated by two coactivators/acetyltransferases, p300 and p300- and CBP-associated factor (P/CAF) in vitro and in vivo. Whereas p300 acetylates two lysine residues (K33 and K116) within the ER81 N-terminal transactivation domain, P/CAF targets only K116. Acetylation of ER81 not only enhances its ability to transactivate but also increases its DNA binding activity and in vivo half-life. Furthermore, oncogenic HER2/Neu, which induces phosphorylation and thereby activation of ER81, was less able to activate acetylation-deficient ER81 mutants, indicating that both acetyltransferase and protein kinase-specific regulatory mechanisms control ER81 activity. Importantly, HER2/Neu overexpression stimulates the ability of p300 to acetylate ER81, likely by inducing phosphorylation of p300 through the Ras→Raf→mitogen-activated protein kinase pathway. This represents a novel mechanism by which oncogenic HER2/Neu, Ras, or Raf may promote tumor formation by enhancing acetylation not only of ER81 but also of other downstream effector transcription factors as well as histones.
机译：ETS转录因子ER81的正常表达是正常发育的先决条件，其失调有助于肿瘤形成。在这里，我们证明了在体外和体内，ER81被两种共激活因子/乙酰基转移酶p300和p300和CBP相关因子（P / CAF）乙酰化。 p300将ER81 N末端反式激活域内的两个赖氨酸残基（K33和K116）乙酰化，而P / CAF仅靶向K116。 ER81的乙酰化不仅增强了它的反式激活能力，而且还增加了其DNA结合活性和体内半衰期。此外，致癌性HER2 / Neu诱导磷酸化从而激活ER81，因此激活乙酰化不足的ER81突变体的能力较弱，表明乙酰基转移酶和蛋白激酶特异性调控机制均能控制ER81的活性。重要的是，HER2 / Neu的过度表达可能刺激p300乙酰化ER81的能力，可能是通过Ras→Raf→有丝分裂原激活的蛋白激酶途径诱导p300磷酸化。这代表了一种新的机制，致癌的HER2 / Neu，Ras或Raf不仅可以通过增强ER81的乙酰化，而且可以增强其他下游效应子转录因子和组蛋白的乙酰化来促进肿瘤形成。

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