Janjua S, Stephanou A, Latchman D S
Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UK.
Cell Death Differ. 2002 Oct;9(10):1140-6. doi: 10.1038/sj.cdd.4401082.
It has previously been demonstrated that the STAT-1 transcription factor plays a key role in apoptosis induced by the cellular regulatory factors interferon gamma and TNF-alpha. Here we demonstrate that cells lacking STAT-1 show reduced cell death/apoptosis in response to stressful stimuli such as heat or ischaemia. Expression of STAT-1 in these cells does not enhance basal cell death but restores sensitivity to stress-induced death whereas this effect is not observed upon over-expression of STAT-3. Enhanced sensitivity to stress-induced cell death requires the C-terminal activation domain of STAT-1 and the phosphorylation sites at tyrosine 701 and serine 727. Moreover, we show for the first time in any system that the isolated C-terminal domain of STAT-1 is able to enhance stress-induced cell death in the absence of the DNA binding domain or any other region of STAT-1. Hence, STAT-1 plays a key role in stress-induced cell death, potentially acting via a novel co-activator-type mechanism and represents a possible therapeutic target for strategies aimed at minimising cell death, for example, following ischaemic injury.
先前已经证明，信号转导和转录激活因子1（STAT-1）转录因子在细胞调节因子γ干扰素和肿瘤坏死因子-α诱导的细胞凋亡中起关键作用。在此我们证明，缺乏STAT-1的细胞在响应热或缺血等应激刺激时，细胞死亡/凋亡减少。在这些细胞中STAT-1的表达不会增强基础细胞死亡，但可恢复对应激诱导死亡的敏感性，而在过表达STAT-3时未观察到这种效应。对应激诱导细胞死亡的敏感性增强需要STAT-1的C末端激活结构域以及酪氨酸701和丝氨酸727的磷酸化位点。此外，我们首次在任何系统中表明，在没有STAT-1的DNA结合结构域或任何其他区域的情况下，分离的STAT-1 C末端结构域能够增强应激诱导的细胞死亡。因此，STAT-1在应激诱导的细胞死亡中起关键作用，可能通过一种新型共激活因子型机制发挥作用，并且代表了旨在最小化细胞死亡（例如在缺血性损伤后）的策略的一个可能治疗靶点。
