Parathyroid Hormone Activation of Matrix Metalloproteinase-13 Transcription Requires the Histone Acetyltransferase Activity of p300 and PCAF and p300-dependent Acetylation of PCAF
Parathyroid Hormone Activation of Matrix Metalloproteinase-13 Transcription Requires the Histone Acetyltransferase Activity of p300 and PCAF and p300-dependent Acetylation of PCAF
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DOI：
10.1074/jbc.m110.142141
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发表时间：
2010-12-03
影响因子：
4.8
通讯作者：
Partridge, Nicola C.
中科院分区：
文献类型：
--
作者：
Lee, Minnkyong;Partridge, Nicola C.
甲状旁腺激素（PTH）调节许多参与成骨细胞骨重塑的基因的转录。这些基因之一是基质金属蛋白酶-13 (MMP-13)，它参与骨重塑和软骨内骨形成的早期阶段。我们之前已经表明，在成骨细胞 UMR106-01 细胞以及原代成骨细胞中，PTH 处理可高度诱导 Mmp-13 基因表达。在这里，我们表明，除了 p300 和 Runx2 之外，p300/CBP 相关因子 (PCAF) 也是 Mmp-13 转录的 PTH 激活所必需的。 PTH 处理后，PCAF 越来越多地募集到 MMP-13 近端启动子区域，这与 RNA 聚合酶 II 募集和组蛋白乙酰化的增加有关。此外，PTH 处理增加了 PCAF 的乙酰化，这一过程需要 p300。 PTH 处理后，UMR 106-01 细胞和原代成骨细胞中，通过 siRNA 敲低 PCAF、p300 或 Runx2 可降低 Mmp-13 mRNA 表达。我们发现 p300 和 PCAF 之间存在相互依赖性，在 PTH 处理后被招募到 Mmp-13 启动子。在启动子报告基因检测中，p300 和 PCAF 对 MMP-13 启动子活性的 PTH 刺激具有累加效应，这需要它们的组蛋白乙酰转移酶活性。我们的研究结果表明，PCAF 作为 PTH 信号转导下游的转录共激活剂，是 PTH 刺激 MMP-13 转录所必需的。 PCAF与p300和Runx2配合介导MMP-13转录的PTH激活。
Parathyroid hormone (PTH) regulates the transcription of many genes involved in bone remodeling in osteoblasts. One of these genes is matrix metalloproteinase-13 (MMP-13), which is involved in bone remodeling and early stages of endochondral bone formation. We have previously shown that Mmp-13 gene expression is highly induced by PTH treatment in osteoblastic UMR106-01 cells, as well as primary osteoblasts. Here, we show that p300/CBP-associated factor (PCAF), in addition to p300 and Runx2, is required for PTH activation of Mmp-13 transcription. PCAF was increasingly recruited to the MMP-13 proximal promoter region after PTH treatment, and this was associated with an increase in RNA polymerase II recruitment and histone acetylation. In addition, PTH treatment increased the acetylation of PCAF, a process that required p300. Knockdown of PCAF, p300, or Runx2 by siRNA decreased Mmp-13 mRNA expression after PTH treatment in both UMR 106-01 cells and primary osteoblasts. We found that there is a mutual dependence between p300 and PCAF to be recruited to the Mmp-13 promoter after PTH treatment. In promoter-reporter assays, p300 and PCAF had an additive effect on PTH stimulation of MMP-13 promoter activity, and this required their histone acetyltransferase activity. Our findings demonstrate that PCAF acts downstream of PTH signaling as a transcriptional coactivator that is required for PTH stimulation of MMP-13 transcription. PCAF cooperates with p300 and Runx2 to mediate PTH activation of MMP-13 transcription.