Transcriptional regulation by transforming growth factor beta of the expression of retinoic acid and retinoid X receptor genes in osteoblastic cells is mediated through AP-1
Transcriptional regulation by transforming growth factor beta of the expression of retinoic acid and retinoid X receptor genes in osteoblastic cells is mediated through AP-1
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DOI：
10.1074/jbc.271.49.31602
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发表时间：
1996-12-06
影响因子：
4.8
通讯作者：
Hanazawa, S
中科院分区：
文献类型：
--
作者：
Chen, Y;Takeshita, A;Hanazawa, S
我们现在报道，转化生长因子p1是一种强大的骨重建调节细胞因子，是成骨细胞MC3T3-E1维甲酸受体(RARs)和维甲酸X受体(RXRs)基因表达的强大刺激因子。转化生长因子-β1转录刺激RARα、RAR Gamma和RXRα基因的表达，但不刺激RARβ、RXRβ和RXR Gamma基因的表达。我们还观察到，转录因子AP-1在转化生长因子-β1刺激的RARα、RARγ和RXRα基因表达的信号通路中发挥重要作用，因为反义c-fos和c-jun的混合物显著抑制了这些基因在细胞因子处理细胞中的表达。凝胶迁移率改变分析表明，转化生长因子-β1能够以剂量依赖的方式增加核蛋白与直接重复序列5的结合，直接重复序列是对RAR-RXR异二聚体具有高亲和力的共同序列。使用针对每个受体的特异性抗体进行的迁移率改变分析表明，直接重复B结合蛋白可能是RAR和RXR亚型。丝氨酸/苏氨酸激酶的抑制剂H-7和AP-1的抑制剂姜黄素都强烈地抑制了与直接重复序列5的刺激结合。本研究提出了一种新的途径，即通过刺激RAR-RXR的转录活性，以配体依赖的方式在成骨细胞中发挥转化生长因子-β1的作用。
We now report that transforming growth factor pi (TGF-PI), a potent regulatory cytokine of bone remodeling, is a powerful stimulator for gene expression of retinoic acid receptors (RARs) and retinoid X receptors (RXRs) in osteoblastic MC3T3-E1 cells. TGF-beta 1 transcriptionally stimulated the expression of RAR alpha, RAR gamma, and RXR alpha genes, but did not do so for RAR beta, RXR beta, and RXR gamma genes. We also observed that AP-1, a transcriptional factor, plays an important role in the signal pathway for expression of RAR alpha, RAR gamma, and RXR alpha genes stimulated by TGF-beta 1 because stimulation of the expression of these genes in the cytokine-treated cells was markedly inhibited by a mixture of antisense c-fos and c-jun. A gel mobility shift assay demonstrated that TGF-beta 1 is able to increase, in a dose-dependent manner, the binding of nuclear proteins to direct repeat 5, a consensus sequence with high affinity for RAR-RXR heterodimers. The mobility shift assay, using specific antibody for each receptor, showed that direct repeat B-binding proteins may be RAR and RXR isoforms. The stimulated binding to direct repeat 5 was inhibited strongly by H-7, an inhibitor of serine/threonine kinase, and by curcumin, an inhibitor of AP-1, The present study suggests a novel pathway for TGF-beta 1 action in osteoblastic cells via stimulation of RAR-RXR transcriptional activity in a ligand-dependent fashion.