Insights into regulation and function of the major stress-induced hsp70 molecular chaperone in vivo:: Analysis of mice with targeted gene disruption of the hsp70.1 or hsp70.3 gene
Insights into regulation and function of the major stress-induced hsp70 molecular chaperone in vivo:: Analysis of mice with targeted gene disruption of the hsp70.1 or hsp70.3 gene
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DOI：
10.1128/mcb.21.24.8575-8591.2001
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发表时间：
2001-12-01
影响因子：
5.3
通讯作者：
Moskophidis, D
中科院分区：
文献类型：
--
作者：
Huang, L;Mivechi, NF;Moskophidis, D
小鼠 hsp70 基因家族包括进化上保守的 hsp70.1 和 hsp70.3 基因，它们是热和其他应激刺激诱导的主要蛋白质。 hsp70.1 和 hsp70.3 编码相同的蛋白质，可保护细胞并促进其从应激引起的损伤中恢复。虽然 hsp70 基因家族已被广泛研究，并且其编码的蛋白质作为分子伴侣在一系列人类病理学中的作用已得到认识，但人们对 hsp70.1 和 hsp70.3 表达的发育调控及其产物的体内生物学功能知之甚少。为了直接研究这些蛋白质在体内的生理作用，我们通过用框内 β-半乳糖苷酶序列替换 hsp70.1 或 hsp70.3 基因，产生了热休克蛋白 70 (hsp70) 缺陷的小鼠。我们在此报告，hsp70.1和hsp70.3的表达在转录水平上受到发育调节，并且在胚胎发育期间和成年小鼠的组织中观察到这两个基因的重叠表达模式。 hsp70.1(-/-)或hsp70.3(-/-)小鼠可存活并具有生育能力，没有明显的形态异常。在胚胎晚期和成年小鼠中，这两种基因在直接暴露于环境的组织（表皮和角膜）和某些内脏器官（舌上皮、食道和前胃，以及肾脏、膀胱和海马）中组成型表达。小鼠暴露于热应激会导致 hsp70 的快速诱导和表达，特别是在非组成型表达 hsp70 的器官（肝脏、胰腺、心脏、肺、肾上腺皮质和肠）中。尽管在单基因缺陷小鼠中通过完整同源基因（即 hsp70.1(-/-) 小鼠中的 hsp70.3，反之亦然）进行功能补偿，但在正常和热应激条件下，在组织中观察到 hsp70 蛋白表达显着减少。在细胞水平上，hsp70.1或hsp70.3的失活导致获得性耐热性维持不足，并增加对热应激诱导的细胞凋亡的敏感性。因此强调了两个hsp70基因的共表达所表现出的加和或协同效应，以及两个hsp70基因的存在的进化意义。
The murine hsp70 gene family includes the evolutionarily conserved hsp70.1 and hsp70.3 genes, which are the major proteins induced by heat and other stress stimuli. hsp70.1 and hsp70.3 encode identical proteins which protect cells and facilitate their recovery from stress-induced damage. While the hsp70 gene family has been widely studied and the roles of the proteins it encodes as molecular chaperones in a range of human pathologies are appreciated, little is known about the developmental regulation of hsp70.1 and hsp70.3 expression and the in vivo biological function of their products. To directly study the physiological role of these proteins in vivo, we have generated mice deficient in heat shock protein 70 (hsp70) by replacing the hsp70.1 or hsp70.3 gene with an in-frame beta -galactosidase sequence. We report here that the expression of hsp70.1 and hsp70.3 is developmentally regulated at the transcriptional level, and an overlapping expression pattern for both genes is observed during embryo development and in the tissues of adult mice. hsp70.1(-/-) or hsp70.3(-/-) mice are viable and fertile, with no obvious morphological abnormalities. In late embryonic stage and adult mice, both genes are expressed constitutively in tissues exposed directly to the environment (the epidermis and cornea) and in certain internal organs (the epithelium of the tongue, esophagus, and forestomach, and the kidney, bladder, and hippocampus). Exposure of mice to thermal stress results in the rapid induction and expression of hsp70, especially in organs not constitutively expressing hsp70 (the liver, pancreas, heart, lung, adrenal cortex, and intestine). Despite functional compensation in the single-gene-deficient mice by the intact homologous gene (i.e., hsp70.3 in hsp70.1(-/-) mice and vice versa), a marked reduction in hsp70 protein expression was observed in tissues under both normal and heat stress conditions. At the cellular level, inactivation of hsp70.1 or hsp70.3 resulted in deficient maintenance of acquired thermotolerance and increased sensitivity to heat stress-induced apoptosis. The additive or synergistic effects exhibited by coexpression of both hsp70 genes, and the evolutionary significance of the presence of both hsp70 genes, is hence underlined.