Fernández-Salas Ester, Suh Kwang S, Speransky Vladislav V, Bowers Wendy L, Levy Joshua M, Adams Tracey, Pathak Kamal R, Edwards Lindsay E, Hayes Daniel D, Cheng Christina, Steven Alasdair C, Weinberg Wendy C, Yuspa Stuart H
Laboratory of Cellular Carcinogenesis and Tumor Promotion, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Mol Cell Biol. 2002 Jun;22(11):3610-20. doi: 10.1128/MCB.22.11.3610-3620.2002.
mtCLIC/CLIC4 (referred to here as mtCLIC) is a p53- and tumor necrosis factor alpha-regulated cytoplasmic and mitochondrial protein that belongs to the CLIC family of intracellular chloride channels. mtCLIC associates with the inner mitochondrial membrane. Dual regulation of mtCLIC by two stress response pathways suggested that this chloride channel protein might contribute to the cellular response to cytotoxic stimuli. DNA damage or overexpression of p53 upregulates mtCLIC and induces apoptosis. Overexpression of mtCLIC by transient transfection reduces mitochondrial membrane potential, releases cytochrome c into the cytoplasm, activates caspases, and induces apoptosis. mtCLIC is additive with Bax in inducing apoptosis without a physical association of the two proteins. Antisense mtCLIC prevents the increase in mtCLIC levels and reduces apoptosis induced by p53 but not apoptosis induced by Bax, suggesting that the two proapoptotic proteins function through independent pathways. Our studies indicate that mtCLIC, like Bax, Noxa, p53AIP1, and PUMA, participates in a stress-induced death pathway converging on mitochondria and should be considered a target for cancer therapy through genetic or pharmacologic approaches.
线粒体氯离子细胞内通道蛋白/氯离子细胞内通道蛋白4（本文简称为mtCLIC）是一种受p53和肿瘤坏死因子α调控的细胞质和线粒体蛋白，属于细胞内氯离子通道的CLIC家族。mtCLIC与线粒体内膜相关联。两条应激反应途径对mtCLIC的双重调控表明，这种氯离子通道蛋白可能有助于细胞对细胞毒性刺激的反应。DNA损伤或p-53的过表达会上调mtCLIC并诱导细胞凋亡。通过瞬时转染使mtCLIC过表达会降低线粒体膜电位，将细胞色素c释放到细胞质中，激活半胱天冬酶，并诱导细胞凋亡。在诱导细胞凋亡方面，mtCLIC与Bax具有相加作用，而这两种蛋白并无物理关联。反义mtCLIC可阻止mtCLIC水平的升高，并减少由p53诱导的细胞凋亡，但不能减少由Bax诱导的细胞凋亡，这表明这两种促凋亡蛋白通过独立的途径发挥作用。我们的研究表明，mtCLIC与Bax、Noxa、p53AIP1和PUMA一样，参与了一条汇聚于线粒体的应激诱导死亡途径，应被视为通过基因或药理学方法进行癌症治疗的靶点。
