Marshansky V, Wang X, Bertrand R, Luo H, Duguid W, Chinnadurai G, Kanaan N, Vu M D, Wu J
Research Center, Notre-Dame Hospital, Center hospitalier universitaire de l'Université de Montréal, University of Montreal, Montreal, Canada.
J Immunol. 2001 Mar 1;166(5):3130-42. doi: 10.4049/jimmunol.166.5.3130.
The mechanism underlying apoptosis induced by proteasome inhibition in leukemic Jurkat and Namalwa cells was investigated in this study. The proteasome inhibitor lactacystin differentially regulated the protein levels of proapoptotic Bcl-2 family members and Bik was accumulated at the mitochondria. Bik overexpression sufficed to induce apoptosis in these cells. Detailed examination along the respiration chain showed that lactacystin compromised a step after complex III, and exogenous cytochrome c could overcome this compromise. Probably as a result, the succinate-stimulated generation of mitochondrial membrane potential was significantly diminished. Bcl-x(L) interacted with Bik in the cells, and Bcl-x(L) overexpression prevented cytochrome c leakage out of the mitochondria, corrected the mitochondrial membrane potential defect, and protected the cells from apoptosis. These results show that proteasomes can modulate apoptosis of lymphocytes by affecting the half-life of Bcl-2 family members, Bik being one of them.
本研究探讨了蛋白酶体抑制诱导白血病Jurkat细胞和Namalwa细胞凋亡的机制。蛋白酶体抑制剂乳胞素对促凋亡Bcl-2家族成员的蛋白水平有不同调节作用，Bik在线粒体中积累。Bik过表达足以诱导这些细胞凋亡。沿呼吸链的详细检测表明，乳胞素损害了复合物III之后的一个步骤，外源性细胞色素c可克服这种损害。可能因此，琥珀酸刺激的线粒体膜电位产生显著降低。Bcl-x(L)在细胞中与Bik相互作用，Bcl-x(L)过表达可防止细胞色素c从线粒体泄漏，纠正线粒体膜电位缺陷，并保护细胞免于凋亡。这些结果表明，蛋白酶体可通过影响Bcl-2家族成员之一Bik的半衰期来调节淋巴细胞凋亡。
