TGFβ-mediated BIM expression and apoptosis are regulated through SMAD3-dependent expression of the MAPK phosphatase MKP2
TGFβ-mediated BIM expression and apoptosis are regulated through SMAD3-dependent expression of the MAPK phosphatase MKP2
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DOI：
10.1038/embor.2008.158
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发表时间：
2008-09-01
期刊：
影响因子：
7.7
通讯作者：
Howe, PhilipH.
中科院分区：
文献类型：
--
作者：
Ramesh, Sneha;Qi, Xiao-Jun;Howe, PhilipH.
转化生长因子-β (TGF beta) 诱导促凋亡蛋白 BIM 的表达，并介导肝细胞和 B 淋巴细胞的凋亡。 BIM 通过涉及 ERK 依赖性磷酸化和泛素介导的蛋白酶体降解的翻译后机制进行调节。在这里，我们发现TGFb通过快速抑制ERK来诱导BIM，从而阻止BIM的磷酸化和降解。 TGFb 通过 SMAD3 依赖性机制，转录诱导立即早期基因编码的丝裂原激活蛋白激酶 (MAPK) 磷酸酶 MKP2，从而减弱 ERK 并促进 BIM 蛋白的积累。在没有 TGFb 的情况下，肝细胞中 MKP2 的过度表达可调节 ERK 介导的 BIM 磷酸化和细胞凋亡，而在源自 MKP2 缺陷小鼠的 pro-B 细胞中，MKP2 的消除可保护细胞免受 TGF β 介导的细胞凋亡，并阻断 TGF β 诱导的 ERK 抑制和 BIM 诱导。此外，在来自SMAD3缺陷小鼠的pro-B细胞中，TGFb对MKP2的诱导、ERK的抑制、BIM的诱导和细胞凋亡不会发生。我们的结果表明，MKP2 通过将 SMAD3 与 ERK 活性和线粒体介导的促凋亡事件的调节联系起来，介导 TGFβ 依赖性细胞凋亡。
Transforming growth factor-beta (TGF beta) induces the expression of the pro-apoptotic protein BIM, and mediates apoptosis in hepatocytes and B lymphocytes. BIM is regulated through a post-translational mechanism involving ERK-dependent phosphorylation and ubiquitin-mediated proteasomal degradation. Here, we show that TGFb induces BIM through its rapid inhibition of ERK, thereby preventing the phosphorylation and degradation of BIM. TGFb, through a SMAD3-dependent mechanism, transcriptionally induces the mitogen-activated protein kinase (MAPK) phosphatase MKP2, encoded by an immediate early gene, to attenuate ERK and promote the accumulation of BIM protein. Overexpression of MKP2 in hepatocytes modulates ERK-mediated phosphorylation of BIM and apoptosis in the absence of TGFb, whereas its ablation in pro-B cells, derived from MKP2-deficient mice, protects cells from TGF beta-mediated apoptosis, and blocks TGF beta-induced ERK inhibition and BIM induction. Furthermore, in pro-B cells derived from SMAD3-deficient mice, induction of MKP2 by TGFb, inhibition of ERK, induction of BIM and apoptosis do not occur. Our results indicate that MKP2 mediates TGF beta-dependent apoptosis by linking SMAD3 to the modulation of ERK activity and mitochondrial-mediated pro-apoptotic events.