Dijkers P F, Medema R H, Lammers J W, Koenderman L, Coffer P J
Department of Pulmonary Diseases, University Medical Center Utrecht, G03.550, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
Curr Biol. 2000 Oct 5;10(19):1201-4. doi: 10.1016/s0960-9822(00)00728-4.
Cell death is regulated mainly through an evolutionarily conserved form of cell suicide termed apoptosis [1]. Deregulation of apoptosis has been associated with cancer, autoimmune diseases and degenerative disorders. Many cells, particularly those of the hematopoietic system, have a default program of cell death and survival that is dependent on the constant supply of survival signals. The Bcl-2 family, which has both pro- and anti-apoptotic members, plays a critical role in regulating cell survival [2]. One family member, the Bcl-2 interacting mediator of cell death (Bim), contains only a protein-interaction motif known as the BH3 domain, allowing it to bind pro-survival Bcl-2 molecules, neutralizing their function [3]. Disruption of the bim gene results in resistance to apoptosis following cytokine withdrawal in leukocytes, indicating that regulation of the pro-apoptotic activity of Bim is critical for maintenance of the default apoptotic program [4]. Here, we report that withdrawal of cytokine results in upregulation of Bim expression concomitant with induction of the apoptotic program in lymphocytes. Activation of the forkhead transcription factor FKHR-L1, previously implicated in regulation of apoptosis in T lymphocytes [5], was sufficient to induce Bim expression. We propose a mechanism by which cytokines promote lymphocyte survival by inhibition of FKHR-L1, preventing Bim expression.
细胞死亡主要通过一种进化上保守的细胞自杀形式即凋亡来调控[1]。凋亡失调与癌症、自身免疫性疾病及退行性疾病相关。许多细胞，尤其是造血系统的细胞，具有依赖于持续生存信号供应的细胞死亡和存活默认程序。具有促凋亡和抗凋亡成员的Bcl-2家族在调控细胞存活中起关键作用[2]。该家族成员之一，细胞死亡的Bcl-2相互作用介质（Bim），仅包含一个称为BH3结构域的蛋白质相互作用基序，使其能够结合促存活Bcl-2分子，中和其功能[3]。bim基因的破坏导致白细胞中细胞因子撤除后对凋亡产生抗性，表明对Bim促凋亡活性的调控对于维持默认凋亡程序至关重要[4]。在此，我们报道细胞因子撤除导致淋巴细胞中Bim表达上调并伴随凋亡程序的诱导。此前认为参与T淋巴细胞凋亡调控的叉头转录因子FKHR-L1的激活足以诱导Bim表达。我们提出一种机制，即细胞因子通过抑制FKHR-L1、阻止Bim表达来促进淋巴细胞存活。
