Transcriptional activation of mouse mast cell protease-7 by activin and transforming growth factor-β is inhibited by microphthalmia-associated transcription factor
Transcriptional activation of mouse mast cell protease-7 by activin and transforming growth factor-β is inhibited by microphthalmia-associated transcription factor
复制标题
DOI：
10.1074/jbc.m306991200
复制
发表时间：
2003-12-26
影响因子：
4.8
通讯作者：
Abe, M
中科院分区：
文献类型：
--
作者：
Funaba, M;Ikeda, T;Abe, M
以前的研究表明，激活素A和转化生长因子-β（1）（TGF-β（1））诱导骨髓来源的培养肥大细胞祖细胞（BMC-MCs）向分化的迁移和形态学变化。在这里，我们展示了在BMCCs中激活素A和TGF-β（1）上调小鼠肥大细胞蛋白酶-7（mMCP-7）（在分化的肥大细胞中表达），以及mmcp-7基因诱导的分子机制。Smad 3是激活素/TGF-β途径的信号介导物，转录激活mmcp-7。小眼症相关转录因子（MITF）是一种主要在肥大细胞、黑素细胞、心脏和骨骼肌中表达的组织特异性转录因子，可抑制Smad 3介导的mmcp-7转录。MITF与Smad 3相关，MITF的C末端和MH 1和Smad 3的连接区是这种关联所必需的。Smad 3和MITF之间的复合物形成对于MITF抑制Smad 3信号传导既不是必要的也不是充分的。MITF抑制Smad 3的MH 2结构域诱导的转录激活。此外，MITF截短的N-末端氨基酸可以与Smad 3结合，但不抑制Smad 3介导的转录。Smad 3的表达水平下降的MITF，但不显性负MITF的共表达，这是由于蛋白酶体蛋白降解。Smad 3蛋白水平的变化与Smad 3介导的信号转导活性的变化相一致。这些发现表明，MITF负调控Smad依赖性激活素/TGF-β信号在组织特异性的方式。
Previous studies have revealed that activin A and transforming growth factor-beta(1) (TGF-beta(1)) induced migration and morphological changes toward differentiation in bone marrow-derived cultured mast cell progenitors (BMC-MCs). Here we show up-regulation of mouse mast cell protease-7 (mMCP-7), which is expressed in differentiated mast cells, by activin A and TGF-beta(1) in BMCMCs, and the molecular mechanism of the gene induction of mmcp-7. Smad3, a signal mediator of the activin/TGF-beta pathway, transcriptionally activated mmcp-7. Microphthalmia-associated transcription factor ( MITF), a tissue-specific transcription factor predominantly expressed in mast cells, melanocytes, and heart and skeletal muscle, inhibited Smad3-mediated mmcp-7 transcription. MITF associated with Smad3, and the C terminus of MITF and the MH1 and linker region of Smad3 were required for this association. Complex formation between Smad3 and MITF was neither necessary nor sufficient for the inhibition of Smad3 signaling by MITF. MITF inhibited the transcriptional activation induced by the MH2 domain of Smad3. In addition, MITF-truncated N-terminal amino acids could associate with Smad3 but did not inhibit Smad3-mediated transcription. The level of Smad3 was decreased by co-expression of MITF but not of dominant-negative MITF, which resulted from proteasomal protein degradation. The changes in the level of Smad3 protein were paralleled by those in Smad3-mediated signaling activity. These findings suggest that MITF negatively regulates Smad-dependent activin/TGF-beta signaling in a tissue-specific manner.