Heat shock of vascular endothelial cells induces an up-regulatory transcriptional response of the thrombomodulin gene that is delayed in onset and does not attenuate.
Heat shock of vascular endothelial cells induces an up-regulatory transcriptional response of the thrombomodulin gene that is delayed in onset and does not attenuate.
复制标题
血管内皮细胞的热休克诱导血栓调节蛋白基因的上调转录反应，该反应延迟发生且不减弱。
DOI：
--
复制
发表时间：
1994
影响因子：
4.8
通讯作者：
R. Jackman
中科院分区：
文献类型：
--
作者：
E. Conway;Lili Liu;Barbara E. Nowakowski;M. Steiner‐Mosonyi;R. Jackman
血栓调节蛋白是一种血管内皮细胞跨膜蛋白，它与凝血酶形成1：1的复合体，这种相互作用的产物构成了具有重要生理意义的天然抗凝系统的基础。血栓调节蛋白的转录下调发生在培养的内皮细胞暴露于细胞因子后，而上调是由维甲酸和二丁酰环腺苷诱导的。血栓调节蛋白在发育过程中也受到调节，出现在7.5天大小鼠胚胎的顶层内胚层中。我们测定了培养的人脐静脉内皮细胞(HUVEC)和A549细胞在持续42℃热休克应激24小时后，细胞表面功能性血栓调节蛋白分别增加了3.2倍和6.7倍。Northern对血栓调节蛋白基因表达的分析也显示出一种延迟反应，其特征是在应激开始后12-18小时开始升高，并在持续热休克的48小时内持续升高，没有减弱。核连续研究证实，增强的主要机制是转录。此外，热休克诱导HUVEC血栓调节蛋白表达上调，阻断了肿瘤坏死因子的抑制作用。对血栓调节蛋白基因5‘端的分析揭示了5个碱基对识别单位的6个高度保守的串联拷贝，这是热休克元件的共同序列。我们假设，应激诱导的血栓调节蛋白基因转录的增强是通过与热休克元件结合的热休克因子介导的，并且血栓调节蛋白的应激反应可能在包括炎症、感染和/或发育在内的各种应激中具有保护血管内皮细胞的生物学作用。
Thrombomodulin is a vascular endothelial cell transmembrane protein that forms a 1:1 complex with thrombin, this interaction product forming the basis of a physiologically important natural anticoagulant system. Transcriptional down-regulation of thrombomodulin occurs following exposure of cultured endothelial cells to cytokines, while up-regulation is induced by retinoic acid and dibutyryl cyclic AMP. Thrombomodulin is also regulated developmentally, appearing in the parietal endoderm of 7.5-day-old mouse embryos. We determined that cell surface functional thrombomodulin in cultured human umbilical vein endothelial cells (HUVEC) and A549 cells increased 3.2- and 6.7-fold, respectively, in response to 24 h of continuous 42 degrees C heat shock stress. Northern analyses of thrombomodulin mRNA accumulation also showed a delayed response that was characterized by an augmentation in mRNA levels that started 12-18 h after the initiation of the stress, and continued to rise, without attenuation, during 48 h of continuous heat shock. Nuclear run-on studies confirmed that the predominant mechanism of augmentation was transcriptional. Furthermore, the heat shock-induced up-regulation of thrombomodulin in HUVEC abrogated the suppressive effect of tumor necrosis factor. Analysis of the 5' region of the thrombomodulin gene revealed six highly conserved tandem copies of the five base pair recognition unit that is the consensus sequence for a heat shock element. We hypothesize that the stress-induced augmentation in thrombomodulin gene transcription is mediated via heat shock factors binding to the heat shock element and that the stress response of thrombomodulin may have a biological role to protect the vascular endothelium during a variety of stresses, including inflammation, infection, and/or development.