Schulz Ramona, Vogel Tanja, Dressel Ralf, Krieglstein Kerstin
Centre of Anatomy, Department of Neuroanatomy, Georg August University, Goettingen, Germany.
Cell Tissue Res. 2008 Dec;334(3):327-38. doi: 10.1007/s00441-008-0714-5. Epub 2008 Nov 11.
Activins and transforming growth factor (TGF)-betas, members of the TGF-beta superfamily, affect numerous physiological processes, including apoptosis, in a variety of organs and tissues. Apoptotic functions of TGF-betas, in contrast to those of the activins, are well documented in the developing and adult nervous system. TGF-betas operate in a context-dependent manner and cooperate with other cytokines in the regulation of apoptosis. In this study, we show, for the first time, an apoptotic function of ActivinA in the nervous system, i.e. in oligodendroglial progenitor cells. Using the oligodendroglial cell line OLI-neu, we show that ActivinA acts autonomously, without cooperating with TGF-beta. In contrast to the mechanism of TGF-beta-mediated apoptosis involving Bcl-xl down-regulation, Bcl-xl in ActivinA-induced apoptosis is classically sequestered by the BH3-only protein Puma. Puma expression is controlled by the transcription factor p53 as demonstrated by experiments with the p53 inhibitor Pifithrin-alpha. Furthermore, in the apoptotic TGF-beta pathway, caspase-3 is activated, whereas in the apoptotic ActivinA pathway, apoptosis-inducing factor is released to trigger DNA fragmentation. These data suggest that TGF-beta and ActivinA induce apoptosis in oligodendrocytes by different apoptotic pathways.
激活素和转化生长因子（TGF）-β属于TGF-β超家族成员，在多种器官和组织中影响包括细胞凋亡在内的众多生理过程。与激活素不同，TGF-β在发育中的和成年神经系统中的凋亡功能已有充分记载。TGF-β以上下文依赖的方式发挥作用，并在细胞凋亡调节中与其他细胞因子协同作用。在本研究中，我们首次展示了激活素A在神经系统即少突胶质前体细胞中的凋亡功能。使用少突胶质细胞系OLI-neu，我们发现激活素A自主发挥作用，无需与TGF-β协同。与TGF-β介导的涉及Bcl-xl下调的凋亡机制不同，在激活素A诱导的凋亡中，Bcl-xl经典地被仅含BH3结构域的蛋白Puma隔离。如使用p53抑制剂Pifithrin-α的实验所示，Puma的表达受转录因子p53控制。此外，在凋亡性TGF-β途径中，半胱天冬酶-3被激活，而在凋亡性激活素A途径中，凋亡诱导因子被释放以触发DNA片段化。这些数据表明，TGF-β和激活素A通过不同的凋亡途径诱导少突胶质细胞凋亡。
