Yin Weihong, Raffelsberger Wolfgang, Gronemeyer Hinrich
Department of Cell Biology and Signal Transduction, Institut de Génétique et de Biologie Moléculaire et Cellulaire/CNRS/INSERM/ULP, BP 10142, F-67404 Illkirch Cedex, C. U. de Strasbourg, France.
Int J Biochem Cell Biol. 2005 Aug;37(8):1696-708. doi: 10.1016/j.biocel.2005.03.003. Epub 2005 Apr 25.
As a single signal, retinoids induce terminal differentiation. This implies that they activate differentiation and apoptosis in a temporally defined order to allow expression of the differentiated phenotype well before death. We report that two apparently contradictory retinoid-induced programs have the capacity to define cellular life span. Anti-apoptotic factors are activated concomitantly with differentiation, while retinoids induce at the same time also pro-apoptotic signaling. We have assessed the roles of two key factors, Bcl2A1 and TRAIL, in the temporal programming of cell death and differentiation. We demonstrate that PLB985 are type II cells in which TRAIL induces apoptosis through the extrinsic and--via Bid activation--also the intrinsic death pathways. Bcl2A1, ectopically over-expressed, or endogenously induced by retinoic acid receptor agonists, protected cells from apoptosis triggered by TRAIL, whose induction required the activation of both the retinoic acid and retinoid X receptors. Bcl2A1 prevented loss of mitochondrial membrane potential and caspase-9, but not caspase-8, activation. The expression of anti-sense Bcl2A1 sensitized PLB985 cells to TRAIL. Co-culture experiments revealed protection from fraternicide if sister cells were pre-exposed to retinoic acid. Collectively, our data support a model in which retinoids orchestrate a life span-regulatory program comprising Bcl2A1 induction to temporally protect against concomitantly induced TRAIL death signaling. Termination of this life span in presence of Bcl2A1 is most likely a consequence of the Bid-independent TRAIL action. Thus, depending on the retinoic acid and retinoid X receptor activation potential of a ligand and the relative efficacies of the intrinsic and extrinsic death pathways in a given cell, a single retinoid triggers the life span of a differentiated phenotype.
作为单一信号，类视黄醇可诱导终末分化。这意味着它们以时间定义的顺序激活分化和凋亡，从而在细胞死亡之前充分表达分化表型。我们报道，两个看似矛盾的类视黄醇诱导程序具有定义细胞寿命的能力。抗凋亡因子在分化的同时被激活，而类视黄醇同时也诱导促凋亡信号。我们评估了两个关键因子Bcl2A1和TRAIL在细胞死亡和分化的时间编程中的作用。我们证明PLB985是II型细胞，其中TRAIL通过外源性途径以及通过Bid激活也通过内源性死亡途径诱导凋亡。异位过表达或由视黄酸受体激动剂内源性诱导的Bcl2A1可保护细胞免受TRAIL触发的凋亡，TRAIL的诱导需要视黄酸和类视黄醇X受体的激活。Bcl2A1可防止线粒体膜电位丧失和caspase-9激活，但不能防止caspase-8激活。反义Bcl2A1的表达使PLB985细胞对TRAIL敏感。共培养实验表明，如果姐妹细胞预先暴露于视黄酸，则可免受同类相残。总体而言，我们的数据支持一种模型，即类视黄醇协调一个寿命调节程序，该程序包括诱导Bcl2A1以暂时保护细胞免受同时诱导的TRAIL死亡信号的影响。在存在Bcl2A1的情况下这种寿命的终止很可能是Bid非依赖性TRAIL作用的结果。因此，根据配体的视黄酸和类视黄醇X受体激活潜力以及给定细胞中内源性和外源性死亡途径的相对效力，单个类视黄醇可触发分化表型的寿命。
