Phosphorylation-dependent sumoylation拮抗去抑制孕酮受体在乳腺癌细胞。
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副检察官丹尼尔AR, EJ,兰格CA
Phosphorylation-dependent sumoylation拮抗去抑制孕酮受体在乳腺癌细胞。
摩尔性。2007;12月21 (12):2890 - 906。Epub 2007年8月23日。
- PubMed ID
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17717077 (在PubMed]
- 文摘
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孕酮受体(PRs)调解在乳房发育和增殖导致乳腺癌的进展,部分通过与多肽生长因子协同加强。我们以前确定公关Ser294作为公关的直接监管的关键站点位置,活动,和营业额磷酸化反应事件。在此,我们试图更好地了解激素相声改变公关的功能。我们证明黄体酮(R5020和RU486)诱导快速sumoylation公关Lys388(15分钟);sumoylation压制公关转录活动选择孕激素响应element-driven和内源性启动子和阻碍ligand-induced公关下调。符合这一发现,我们表明,稳定但弱活跃phospho-mutant S294A PRs严重sumoylated。相反,desumoylated公关,由突变的公关Lys388 (K388R)或超表达的sentrin(相扑)特殊蛋白酶desumoylating酶,是低孕酮浓度非常敏感。K388R和S294A突变(KRSA double-mutant PR)救助转录和周转率phospho-mutant受损(S294A)受体。值得注意的是,磷酸化事件对抗PR-B但不是PR-A sumoylation。治疗细胞表皮生长因子或瞬态的表达激活增殖/ ERK激酶激酶或细胞周期蛋白依赖性蛋白激酶2诱发PR-B Ser294磷酸化和块PR-B sumoylation,从而derepressing受体活动; PR-A is resistant to these events. Modulation of reversible PR sumoylation in response to diverse hormonal signals provides a mechanism for rapid isoform-specific changes in hormone responsiveness. In the context of elevated protein kinase activities, such as during mammary gland development or breast cancer progression, phosphorylated PR-B may be undersumoylated, transcriptionally hyperactive, and unstable/undetectable.