【摘要】：機(jī)體通過(guò)細(xì)胞凋亡機(jī)制選擇性地清除體內(nèi)無(wú)用的細(xì)胞,以維持細(xì)胞增殖和細(xì)胞死亡之間的精密平衡。因此,細(xì)胞凋亡在個(gè)體的生長(zhǎng)發(fā)育以及存活過(guò)程中起著重要作用。細(xì)胞器內(nèi)質(zhì)網(wǎng)(endoplasmic reticulum,ER)主要參與蛋白的合成、折疊以及轉(zhuǎn)運(yùn)過(guò)程,并調(diào)節(jié)細(xì)胞應(yīng)激反應(yīng)和細(xì)胞內(nèi)鈣離子水平。近年來(lái)的研究表明內(nèi)質(zhì)網(wǎng)與線粒體、溶酶體相似,是參與細(xì)胞凋亡的重要細(xì)胞器之一。內(nèi)質(zhì)網(wǎng)主要通過(guò)兩種機(jī)制參與細(xì)胞凋亡,即未折疊蛋白反應(yīng)(unfolded protein response,UPR)和Ca~(2+)信號(hào)。內(nèi)質(zhì)網(wǎng)中的Ca~(2+)穩(wěn)態(tài)改變和未折疊蛋白的積累均可誘導(dǎo)內(nèi)質(zhì)網(wǎng)應(yīng)激反應(yīng),最終可導(dǎo)致細(xì)胞凋亡的發(fā)生。本研究從人骨髓基質(zhì)細(xì)胞cDNA文庫(kù)中自主分離了一種新型凋亡相關(guān)分子,該分子穩(wěn)定表達(dá)可增加L929細(xì)胞對(duì)TNF-α誘導(dǎo)凋亡作用的敏感性。我們結(jié)合實(shí)驗(yàn)結(jié)果推測(cè)其參與細(xì)胞凋亡的可能機(jī)制為:該分子向內(nèi)質(zhì)網(wǎng)發(fā)生部分轉(zhuǎn)位,從而可能誘發(fā)內(nèi)質(zhì)網(wǎng)的凋亡改變,隨后內(nèi)質(zhì)網(wǎng)可能直接或間接地引起下游線粒體改變包括線粒體電勢(shì)差(mitochondrial membrane potential,△Ψm)的下降和凋亡誘導(dǎo)因子(apoptosis inducing factor,AIE)的釋放,最終導(dǎo)致caspase非依賴的細(xì)胞凋亡。結(jié)合該分子含有PH和FYVE功能域的結(jié)構(gòu)特征,將其命名為含有PH結(jié)構(gòu)域和FYVE結(jié)構(gòu)域的、與內(nèi)質(zhì)網(wǎng)有關(guān)的凋亡相關(guān)蛋白即EAPF ((?)ndoplasmic reticulum-associated (?)poptosis-involved protein containing (?)H and (?)YVE domains)。
文內(nèi)圖片：
圖片說(shuō)明：Phafin一2亞家族成員與PH、FYVE結(jié)構(gòu)域的多重比較
[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- 偽. 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.
【學(xué)位授予單位】：浙江大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2005
【分類號(hào)】：R341

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