ER stress triggers apoptosis by activating BH3-only protein Bim (Cell, 2007, 129:1337-1349)

報告日期: 2007/10/12
報告時間: 15:10/16:00
報告學生: 羅苑菁
講評老師: 徐麗君
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ER Stress Triggers Apoptosis by Activating BH3-Only Protein Bim

Cell. 129:1337-1349, 2007

 

Speaker: 羅苑菁  

Commentator: 徐麗君 老師

Time: 2007/10/12 15:10~16:00

Place: Room 602

 

Abstract:

   ER stress was provoked by a variety condition, such as impairment of protein folding and secretion, alteration of Ca2+ homeostasis, and viral infection. The persistent ER stress will induce cell apoptosis mediated by caspase-12, CHOP, and proapoptotic BH3-only proteins. Previously studies showed that Bim, a member of BH3-only protein family, was essential for cell apoptosis upon treating diverse death stimuli, such as cytokine deprivation, Ca2+ ionophore ionomycin or microtubule-stabilizer taxol. However, it remains unknown whether the Bim protein could participate in ER stress-induced apoptosis. In this study, the authors observed that the protein and mRNA level of Bim was specifically upregulated by treating with ER stress inducer thapsigargin or tunicamycin in MCF-7 breast carcinoma-derived cells. The resistance to thapsigargin-induced apoptosis was measured in Bim-deficient thymocytes and Bim RNAi-expressed MCF-7 cells. Next, the authors found that the dephosphorylation of Bim protein by phosphatase PP2A resulted in accumulation of Bim without subsequently ubiquitination and proteasomal degradation during ER stress. The CHOP-C/EBPa directly binding to the promoter region of bim was demonstrated by luciferase assay and electrophoretic mobility shift assays (EMSA). Therefore, the transcriptional upregulation of bim was mediated by CHOP-C/EBPa heterodimers. CHOP-deficient macrophages failed to upregulate Bim upon treating with thapsigargin. Furthermore, Bim-deficient mice could prevent from extensive apoptosis of kidney epithelial cells with intraperitoneal injection of tunicamycin. Based on these results, the authors concluded that the Bim regulated by phosphatase PP2A and CHOP-C/EBPa was necessary in the ER stress-induced apoptosis. It was speculated that the Bim and its regulatory molecules may be the therapeutic targets for ER stress-related diseases, for example, liver disease with a1-antitrypsin deficiency.

 

References:

Bouillet, P. Metcalf, D., et al. (1999). Proapoptotic Bcl-2 relative Bim reguired for certain apoptotic response, leukocyte homeostasis, and to preclude autoimmunity. Science. 286:1735-1738.

 

Rutkowski, D.M.,and Kaufman, R.J. (2004). A trip to the ER: coping with stress. TRENDS in Cell Biology. 14, 20-28.