Kucharczak J F, Simmons M J, Duckett C S, Gélinas C
Center for Advanced Biotechnology and Medicine, UMDNJ-Robert Wood Johnson Medical School, Piscataway, NJ 08854-5638, USA.
Cell Death Differ. 2005 Sep;12(9):1225-39. doi: 10.1038/sj.cdd.4401684.
Bfl-1/A1 is generally recognized as a Bcl-2-related inhibitor of apoptosis. We show that Bfl-1 undergoes constitutive ubiquitin/proteasome-mediated turnover. Moreover, while Bfl-1 suppresses apoptosis induced by staurosporine or cytokine withdrawal, it is proapoptotic in response to tumor necrosis factor (TNF) receptor activation in FL5.12 pro-B cells. Its anti- versus proapoptotic effect is regulated by two proteolytic events: (1) its constitutive proteasome-mediated turnover and (2) its TNF/cycloheximide (CHX)-induced cleavage by mu-calpain, or a calpain-like activity, coincident with acquisition of a proapoptotic phenotype. In vitro studies suggest that calpain-mediated cleavage of Bfl-1 occurs between its Bcl-2 homology (BH)4 and BH3 domains. This would be consistent with the generation of a proapoptotic Bax-like BH1-3 molecule. Overall, our studies uncovered two new regulatory mechanisms that play a decisive role in determining Bfl-1's prosurvival versus prodeath activities. These findings might provide important clues to counteract chemoresistance in tumor cells that highly express Bfl-1.
Bfl-1/A1通常被认为是一种与Bcl-2相关的凋亡抑制因子。我们发现Bfl-1会经历组成型泛素/蛋白酶体介导的周转。此外，虽然Bfl-1能抑制星形孢菌素或细胞因子撤除诱导的凋亡，但在FL5.12前B细胞中，它对肿瘤坏死因子（TNF）受体激活具有促凋亡作用。其抗凋亡与促凋亡作用受两种蛋白水解事件调控：（1）其组成型蛋白酶体介导的周转；（2）其TNF/放线菌酮（CHX）诱导的被μ-钙蛋白酶或类似钙蛋白酶活性的切割，这与获得促凋亡表型同时发生。体外研究表明，钙蛋白酶介导的Bfl-1切割发生在其Bcl-2同源（BH）4和BH3结构域之间。这与产生一种促凋亡的Bax样BH1-3分子相一致。总体而言，我们的研究揭示了两种新的调控机制，它们在决定Bfl-1的促生存与促死亡活性方面起决定性作用。这些发现可能为对抗高表达Bfl-1的肿瘤细胞的化学抗性提供重要线索。
