Intracellular leucine-rich alpha-2-glycoprotein-1 competes with Apaf-1 for binding cytochrome c in protecting MCF-7 breast cancer cells from apoptosis.
Intracellular leucine-rich alpha-2-glycoprotein-1 competes with Apaf-1 for binding cytochrome c in protecting MCF-7 breast cancer cells from apoptosis.
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细胞内富含亮氨酸的α-2-糖蛋白-1与Apaf-1竞争结合细胞色素c保护MCF-7乳腺癌细胞免于凋亡
DOI：
10.1007/s10495-020-01647-9
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发表时间：
2021-03
期刊：
影响因子：
--
通讯作者：
Kelekar A
中科院分区：
文献类型：
--
作者：
Jemmerson R;Staskus K;Higgins L;Conklin K;Kelekar A
富含亮氨酸的α-2-糖蛋白-1（LRG 1）与凋亡激活因子-1（Apaf-1）竞争结合细胞色素c（Cyt c），在抑制细胞凋亡中发挥作用。采用MCF-7乳腺癌细胞，我们报告说，细胞内LRG 1保护细胞凋亡。因此，细胞转染lrg 1基因和表达更高水平的LRG 1更耐过氧化氢诱导的细胞凋亡比亲本细胞，而细胞中LRG mRNA被敲低短发夹（sh）RNA诱导的降解更敏感。与Apaf-1从凋亡细胞的胞质溶胶共免疫沉淀的Cyt c的量与LRG 1表达水平呈负相关。在lrg 1转染的细胞中，部分糖基化的LRG 1被发现在胞质中，并有一个增加，在活lrg 1转染的细胞相对于亲本细胞胞质中的Cyt c。然而，细胞凋亡不是自发诱导的，因为Cyt c与LRG 1结合，而不是Apaf-1。Cyt c是唯一可检测到的与LRG 1共免疫沉淀的蛋白质。在过氧化氢处理后，LRG 1的降解允许诱导细胞凋亡。我们建议，细胞内LRG 1提高了细胞质细胞色素c诱导凋亡所需的阈值，因此，防止细胞中细胞色素c从线粒体释放的内在途径的发生，而不是由承诺的凋亡信号。LRG 1提供的这种存活机制可能与几个研究小组报道的其细胞外存活功能不同。
Leucine-rich alpha-2-glycoprotein-1 (LRG1) has been shown to compete with apoptosis activating factor-1 (Apaf-1) for binding cytochrome c (Cyt c) and could play a role in inhibition of apoptosis. Employing MCF-7 breast cancer cells, we report that intracellular LRG1 does protect against apoptosis. Thus, cells transfected with the lrg1 gene and expressing higher levels of LRG1 were more resistant to hydrogen peroxide-induced apoptosis than parental cells, while cells in which LRG mRNA was knocked down by short hairpin (sh) RNA-induced degradation were more sensitive. The amount of Cyt c co-immunoprecipitated with Apaf-1 from the cytosol of apoptotic cells was inversely related to the level of LRG1 expression. In lrg1-transfected cells partially-glycosylated LRG1 was found in the cytosol and there was an increase in cytosolic Cyt c in live lrg1-transfected cells relative to parental cells. However, apoptosis was not spontaneously induced because Cyt c was bound to LRG1 and not to Apaf-1. Cyt c was the only detectable protein co-immunoprecipitated with LRG1. Following hydrogen peroxide treatment degradation of LRG1 allowed for induction of apoptosis. We propose that intracellular LRG1 raises the threshold of cytoplasmic Cyt c required to induce apoptosis and, thus, prevents onset of the intrinsic pathway in cells where Cyt c release from mitochondria does not result from committed apoptotic signaling. This mechanism of survival afforded by LRG1 is likely to be distinct from its extracellular survival function that has been reported by several research groups.
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影响因子：
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