一种新型凋亡相关蛋白EAPF的克隆及功能研究

发布时间：2019-07-04 13:02

【摘要】：机体通过细胞凋亡机制选择性地清除体内无用的细胞,以维持细胞增殖和细胞死亡之间的精密平衡。因此,细胞凋亡在个体的生长发育以及存活过程中起着重要作用。细胞器内质网(endoplasmic reticulum,ER)主要参与蛋白的合成、折叠以及转运过程,并调节细胞应激反应和细胞内钙离子水平。近年来的研究表明内质网与线粒体、溶酶体相似,是参与细胞凋亡的重要细胞器之一。内质网主要通过两种机制参与细胞凋亡,即未折叠蛋白反应(unfolded protein response,UPR)和Ca~(2+)信号。内质网中的Ca~(2+)稳态改变和未折叠蛋白的积累均可诱导内质网应激反应,最终可导致细胞凋亡的发生。本研究从人骨髓基质细胞cDNA文库中自主分离了一种新型凋亡相关分子,该分子稳定表达可增加L929细胞对TNF-α诱导凋亡作用的敏感性。我们结合实验结果推测其参与细胞凋亡的可能机制为:该分子向内质网发生部分转位,从而可能诱发内质网的凋亡改变,随后内质网可能直接或间接地引起下游线粒体改变包括线粒体电势差(mitochondrial membrane potential,△Ψm)的下降和凋亡诱导因子(apoptosis inducing factor,AIE)的释放,最终导致caspase非依赖的细胞凋亡。结合该分子含有PH和FYVE功能域的结构特征,将其命名为含有PH结构域和FYVE结构域的、与内质网有关的凋亡相关蛋白即EAPF ((?)ndoplasmic reticulum-associated (?)poptosis-involved protein containing (?)H and (?)YVE domains)。
文内图片：

图片说明：Phafin一2亚家族成员与PH、FYVE结构域的多重比较
[Abstract]:The body selectively removes useless cells through apoptosis mechanism in order to maintain the precise balance between cell proliferation and cell death. Therefore, apoptosis plays an important role in the growth, development and survival of individuals. Organelle endoplasmic reticulum (endoplasmic reticulum,ER) is mainly involved in protein synthesis, folding and transport, and modulates cell stress response and intracellular calcium level. Recent studies have shown that endoplasmic reticulum is similar to mitochondria and lysosome and is one of the important organelle involved in apoptosis. Endoplasmic reticulum (endoplasmic reticulum) is mainly involved in apoptosis through two mechanisms, unfolded protein response (unfolded protein response,UPR and Ca~ (2) signal. The homeostasis of Ca~ (2) in endoplasmic reticulum and the accumulation of unfolded proteins can induce endoplasmic reticulum stress reaction, which can eventually lead to apoptosis. In this study, a novel apoptosis-related molecule was isolated from cDNA library of human bone marrow stroma cells. The stable expression of this molecule can increase the sensitivity of L929 cells to apoptosis induced by TNF- 伪. Based on the experimental results, we speculate that the possible mechanism of its involvement in apoptosis is that the molecule is partially translocated into endoplasmic reticulum, which may induce the apoptosis of endoplasmic reticulum, and then endoplasmic reticulum may directly or indirectly cause the decrease of downstream mtDNA, including the decrease of mitochondrial potential difference (mitochondrial membrane potential, 蠁 m) and the release of apoptosis inducer (apoptosis inducing factor,AIE), which may eventually lead to apoptosis independent of caspase. Combined with the structural characteristics of PH and FYVE domain, it was named EAPF (ndoplasmic reticulum-associated (?) poptosis-involved protein containing () H and () YVE domains)., which contains PH domain and FYVE domain, and is related to endoplasmic reticulum.
【学位授予单位】：浙江大学
【学位级别】：博士
【学位授予年份】：2005
【分类号】：R341

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