CHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum
CHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum
复制标题
DOI：
10.1101/gad.12.7.982
复制
发表时间：
1998-04-01
影响因子：
10.5
通讯作者：
Ron, D
中科院分区：
文献类型：
--
作者：
Zinszner, H;Kuroda, M;Ron, D
细胞应激，尤其是对扰乱内质网功能的毒性和代谢损伤的反应(内质网应激)，是转录因子CHOP的强大诱导者。在通过CHOP基因同源重组获得的小鼠缺乏症模型中，研究了CHOP在细胞对内质网应激相关损伤的反应中的作用。与野生型相比，来自CHOP-/-动物的小鼠胚胎成纤维细胞(MEF)在受到干扰ER功能的药物刺激时，程序性细胞死亡显著减少。在缺乏CHOP的主要二聚化伙伴C/EBPβ的MEF中，也观察到响应内质网应激的程序性细胞死亡的类似缺陷，这表明CHOP-C/EBP途径参与了程序性细胞死亡。为研究CHOP对内质网应激反应的影响，建立了一种动物模型。这需要将具有特定CHOP基因型的小鼠暴露于一次亚致死剂量的衣霉素腹腔注射，并导致以一过性肾功能不全为特征的严重疾病。在CHOP+/+和CHOP+/-小鼠中，这与CHOP在近端小管的早期表达有关，随后出现了类似于人类急性肾小管坏死的组织学图像，这一过程通过细胞再生得以解决。在CHOP-/-动物中，尽管肾功能受到严重损害，但与野生型相比，肾脏中细胞死亡的证据较少。在CHOP-/-动物的近端小管上皮中，TUNEL阳性细胞(细胞程序性死亡的标志)的水平降低了四倍，随后再生的证据明显减少。因此，CHOP在与内质网失灵相关的条件下诱导细胞死亡中起作用，在这种情况下也可能在细胞再生中起作用。
Cellular stress, particularly in response to toxic and metabolic insults that perturb function of the endoplasmic reticulum (ER stress), is a powerful inducer of the transcription factor CHOP. The role of CHOP in the response of cells to injury associated with ER stress was examined in a murine deficiency model obtained by homologous recombination at the chop gene. Compared with the wild type, mouse embryonic fibroblasts (MEFs) derived from chop -/- animals exhibited significantly less programmed cell death when challenged with agents that perturb ER function. A similar deficit in programmed cells death in response to ER stress was also observed in MEFs that lack CHOP's major dimerization partner, C/EBP beta, implicating the CHOP-C/EBP pathway in programmed cell death. An animal model for studying the effects of chop on the response to ER stress was developed. It entailed exposing mice with defined chop genotypes to a single sublethal intraperitoneal injection of tunicamycin and resulted in a severe illness characterized by transient renal insufficiency. In chop +/+ and chop +/- mice this was associated with the early expression of CHOP in the proximal tubules followed by the development of a histological picture similar to the human condition known as acute tubular necrosis, a process that resolved by cellular regeneration. In the chop -/- animals, in spite of the severe impairment in renal function, evidence of cellular death in the kidney was reduced compared with the wild type. The proximal tubule epithelium of chop -/- animals exhibited fourfold lower levels of TUNEL-positive cells (a marker for programmed cell death), and significantly less evidence for subsequent regeneration. CHOP therefore has a role in the induction of cell death under conditions associated with malfunction of the ER and may also have a role in cellular regeneration under such circumstances.