Transforming growth factor beta (TGFbeta)-induced apoptosis: the rise & fall of Bim.
Transforming growth factor beta (TGFbeta)-induced apoptosis: the rise & fall of Bim.
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DOI：
10.4161/cc.8.1.7291
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发表时间：
2009-01-01
期刊：
影响因子：
--
通讯作者：
Howe PH
中科院分区：
文献类型：
--
作者：
Ramesh S;Wildey GM;Howe PH
转化生长因子β（TGFβ）调节细胞增殖、分化和凋亡等基本细胞功能。TGFβ诱导的细胞凋亡涉及多种凋亡介质和信号通路。Bim是一种仅含BH 3的蛋白质，对多种细胞类型的凋亡至关重要。在静息细胞中，BimEL表达水平（主要和最丰富的同种型）受Erk 1/2介导的磷酸化控制，其靶向BimEL进行泛素化和降解。我们先前报道TGFβ通过Smad 3依赖性机制诱导促凋亡蛋白Bim的表达，从而诱导B淋巴细胞的细胞死亡。许多研究表明，TGFβ在许多细胞类型中引起Bim的转录诱导。最近，我们证明，除了其对Bim的转录作用，TGFβ诱导MAPK磷酸酶（MKP），MKP 2/DUSP 4，通过Erk 1/2失活快速增加BimEL水平，导致BimEL去磷酸化和逃避泛素介导的降解。我们的发现不仅在我们暗示TGFβ通过翻译后即时调节机制和通过转录诱导的长期作用来增加BimEL水平的背景下是重要的，而且在暗示MKP作为细胞凋亡中的调节参与者的背景下也是重要的。本文总结了这些最新发现及其对我们理解TGFβ如何介导凋亡的意义，并探讨了控制Bim表达水平的可能调控机制。
Transforming growth factor β (TGFβ) regulates essential cellular functions such as cellular proliferation, differentiation and apoptosis. Multiple apoptotic mediators and signaling pathways have been implicated in TGFβ-induced apoptosis. Bim, a BH3-only protein, is critical for apoptosis in a variety of cell types. In resting cells, BimEL expression levels, the major and most abundant isoform, are controlled by Erk1/2-mediated phosphorylation, which targets BimEL for ubiquitination and degradation. We previously reported that TGFβ induces the expression of the pro-apoptotic protein Bim through a Smad3-dependent mechanism to induce cell death in B-lymphocytes. A number of studies have shown TGFβ to cause transcriptional induction of Bim in many cell types. Recently, we demonstrated that, in addition to its transcriptional effects on Bim, TGFβ induces a MAPK phosphatase (MKP), MKP2/DUSP4, to rapidly increase BimEL levels by inactivation of Erk1/2, resulting in dephosphorylation and escape of BimEL from ubiquitin-mediated degradation. Our findings are of importance not only in the context that we implicate TGFβ to increase BimEL levels through both an immediate post-translational regulatory mechanism and a long-term effect through transcriptional induction, but also in the context of implicating MKPs as regulatory players in apoptosis. Here we summarize these recent findings and their significance to our understanding of how TGFβ mediates apoptosis, and we explore the possible regulatory mechanisms controlling Bim expression levels.
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