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首页> 外文期刊>Molecular and Cellular Biology >Phosphatidylinositol 3-Kinase/Protein Kinase Cζ-Induced Phosphorylation of Sp1 and p107 Repressor Release Have a Critical Role in Histone Deacetylase Inhibitor-Mediated Depression of Transcription of the Luteinizing Hormone Receptor Gene
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Phosphatidylinositol 3-Kinase/Protein Kinase Cζ-Induced Phosphorylation of Sp1 and p107 Repressor Release Have a Critical Role in Histone Deacetylase Inhibitor-Mediated Depression of Transcription of the Luteinizing Hormone Receptor Gene

机译：磷脂酰肌醇3-激酶/蛋白激酶Cζ诱导的Sp1和p107阻遏物释放的磷酸化在组蛋白脱乙酰基酶抑制剂介导的促黄体生成激素受体基因的转录抑制中起关键作用

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We have demonstrated that silencing of luteinizing hormone receptor (LHR) gene transcription is mediated via a proximal Sp1 site at its promoter. Trichostatin A (TSA) induced histone acetylation and gene activation in JAR cells that prevailed in the absence of changes in Sp1/Sp3 expression, their binding activity, disassociation of the histone deacetylase/mSin3A complex from the Sp1 site, or demethylation of the promoter. This indicated a different mechanism involved in TSA-induced derepression. The present studies have revealed that phosphatidylinositol 3-kinase/protein kinase Cζ (PI3K/PKCζ)-mediated Sp1 phosphorylation accounts for Sp1 site-dependent LHR gene activation. TSA caused marked phosphorylation of Sp1 at serine 641 in JAR and MCF-7 cells. Blockade of PI3K or PKCζ activity by specific inhibitors, kinase-deficient mutants, or small interfering RNA abolished the effect of TSA on the LHR gene and Sp1 phosphorylation. PKCζ was shown to associate with Sp1, and this association was enhanced by TSA. Sp1 phosphorylation at serine 641 was required for the release of the pRb homologue p107 from the LHR gene promoter, while p107 acted as a repressor of the LHR gene. Inhibition of PKCζ activity blocked the dissociation of p107 from the LHR gene promoter and markedly reduced Sp1 phosphorylation and transcription. These results have demonstrated that phosphorylation of Sp1 by PI3K/PKCζ is critical for TSA-activated LHR gene expression. These studies have revealed a novel mechanism of TSA action through derecruitment of a repressor from the LHR gene promoter in a PI3K/PKCζ-induced Sp1 phosphorylation-dependent manner.
机译：我们已经证明，促黄体生成激素受体（LHR）基因转录的沉默是通过其启动子附近的Sp1位点介导的。 Trichostatin A（TSA）诱导JAR细胞中的组蛋白乙酰化和基因激活，这种情况普遍存在于Sp1 / Sp3表达，其结合活性，组蛋白脱乙酰基酶/ mSin3A复合物与Sp1位点的解离或启动子去甲基化等方面。这表明参与TSA诱导的抑制的机制不同。目前的研究表明，磷脂酰肌醇3激酶/蛋白激酶Cζ（PI3K /PKCζ）介导的Sp1磷酸化是Sp1位点依赖性LHR基因激活的原因。 TSA引起JAR和MCF-7细胞中丝氨酸641处Sp1的明显磷酸化。特异性抑制剂，激酶缺陷型突变体或小的干扰RNA对PI3K或PKCζ活性的阻断消除了TSA对LHR基因和Sp1磷酸化的影响。 PKCζ被证明与Sp1关联，并且该关联被TSA增强。从LHR基因启动子释放pRb同源物p107时需要丝氨酸641处的Sp1磷酸化，而p107充当LHR基因的阻遏物。 PKCζ活性的抑制阻止了p107从LHR基因启动子的解离，并显着降低了Sp1的磷酸化和转录。这些结果表明，PI3K /PKCζ对Sp1的磷酸化对于TSA激活的LHR基因表达至关重要。这些研究已经揭示了通过以PI3K /PKCζ诱导的Sp1磷酸化依赖性方式从LHR基因启动子上取消阻遏物而使TSA起作用的新机制。

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