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首页> 外文期刊>Molecular and Cellular Biology >Regulation of the Bone-Specific Osteocalcin Gene by p300 Requires Runx2/Cbfa1 and the Vitamin D3 Receptor but Not p300 Intrinsic Histone Acetyltransferase Activity
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Regulation of the Bone-Specific Osteocalcin Gene by p300 Requires Runx2/Cbfa1 and the Vitamin D3 Receptor but Not p300 Intrinsic Histone Acetyltransferase Activity

机译：p300对骨特异性骨钙素基因的调节需要Runx2 / Cbfa1和维生素D3受体，但不需要p300内在组蛋白乙酰转移酶活性

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p300 is a multifunctional transcriptional coactivator that serves as an adapter for several transcription factors including nuclear steroid hormone receptors. p300 possesses an intrinsic histone acetyltransferase (HAT) activity that may be critical for promoting steroid-dependent transcriptional activation. In osteoblastic cells, transcription of the bone-specific osteocalcin (OC) gene is principally regulated by the Runx2/Cbfa1 transcription factor and is stimulated in response to vitamin D3 via the vitamin D3 receptor complex. Therefore, we addressed p300 control of basal and vitamin D3-enhanced activity of the OC promoter. We find that transient overexpression of p300 results in a significant dose-dependent increase of both basal and vitamin D3-stimulated OC gene activity. This stimulatory effect requires intact Runx2/Cbfa1 binding sites and the vitamin D-responsive element. In addition, by coimmunoprecipitation, we show that the endogenous Runx2/Cbfa1 and p300 proteins are components of the same complexes within osteoblastic cells under physiological concentrations. We also demonstrate by chromatin immunoprecipitation assays that p300, Runx2/Cbfa1, and 1α,25-dihydroxyvitamin D3 receptor interact with the OC promoter in intact osteoblastic cells expressing this gene. The effect of p300 on the OC promoter is independent of its intrinsic HAT activity, as a HAT-deficient p300 mutant protein up-regulates expression and cooperates with P/CAF to the same extent as the wild-type p300. On the basis of these results, we propose that p300 interacts with key transcriptional regulators of the OC gene and bridges distal and proximal OC promoter sequences to facilitate responsiveness to vitamin D3.
机译：p300是多功能转录共激活因子，可充当多种转录因子（包括核甾体激素受体）的衔接子。 p300具有固有的组蛋白乙酰转移酶（HAT）活性，这对于促进类固醇依赖性转录激活可能至关重要。在成骨细胞中，骨特异性骨钙素（OC）基因的转录主要受Runx2 / Cbfa1转录因子调控，并通过维生素D 3 < / sub>受体复合物。因此，我们研究了OC启动子的基础和维生素D 3 增强活性的p300控制。我们发现，p300的瞬时过表达导致基础和维生素D 3 刺激的OC基因活性均显着剂量依赖性增加。这种刺激作用需要完整的Runx2 / Cbfa1结合位点和维生素D反应因子。此外，通过共免疫沉淀，我们显示内源性Runx2 / Cbfa1和p300蛋白是成骨细胞在生理浓度下相同复合物的成分。我们还通过染色质免疫沉淀试验证明，p300，Runx2 / Cbfa1和1α，25-二羟基维生素D 3 受体与表达该基因的完整成骨细胞中的OC启动子相互作用。 p300对OC启动子的作用与其内在的HAT活性无关，因为HAT缺失的p300突变蛋白上调表达并与P / CAF协同作用的程度与野生型p300相同。根据这些结果，我们建议p300与OC基因的关键转录调节因子相互作用，并桥接远端和近端OC启动子序列，以促进对维生素D 3 的响应。

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