【摘要】：NRAGE(neurotrophin receptor-interacting MAGE homolog)是MAGE(黑色素瘤抗原)家族的一員。大部分MAGE家族的蛋白僅在腫瘤中表達(dá)，而NRAGE卻在發(fā)育早期和成年期的許多組織中都有表達(dá)，在某些類(lèi)型的腫瘤中NRAGE的表達(dá)量較低。近來(lái)研究表明，NRAGE能夠通過(guò)自身的六肽重復(fù)區(qū)WQXPXX和MAGE家族保守區(qū)(MHD)同多種蛋白結(jié)合，發(fā)揮不同的作用：包括與神經(jīng)生長(zhǎng)因子受體(p75NTR)、X染色體相連的凋亡抑制蛋白(XIAP)、UNC5H1、朊病毒蛋白(PrPc)等蛋白結(jié)合，調(diào)節(jié)細(xì)胞的增殖和凋亡；與necdin、Msx2蛋白結(jié)合促進(jìn)C2C12細(xì)胞向肌細(xì)胞的分化，同時(shí)可以與Ror2蛋白結(jié)合，調(diào)節(jié)自身在細(xì)胞內(nèi)的分布。但有關(guān)NRAGE調(diào)控細(xì)胞信號(hào)通路的研究并不確切，目前的研究?jī)H局限于NRAGE對(duì)細(xì)胞凋亡與骨細(xì)胞分化的作用。于是我們系統(tǒng)地研究了NRAGE對(duì)細(xì)胞凋亡、粘附、分化的作用及相關(guān)機(jī)制。我們研究發(fā)現(xiàn)： 1．NRAGE能夠調(diào)控p53信號(hào)通路。NRAGE通過(guò)自身的六肽重復(fù)區(qū)WQXPXX和MAGE家族保守區(qū)(MHD)與Mdm2競(jìng)爭(zhēng)直接結(jié)合于非磷酸化的p53的N端，抑制Mdm2對(duì)p53的泛素化降解，提高p53的穩(wěn)定性，促進(jìn)p53下游基因p21~(CIP1/WAF1)的表達(dá)，抑制細(xì)胞周期在G0／G1和G2／M期轉(zhuǎn)換時(shí)發(fā)生阻滯，促進(jìn)在UV刺激下由p53介導(dǎo)的細(xì)胞凋亡。 2．NRAGE能夠促使β-catenin由細(xì)胞膜分布轉(zhuǎn)移到細(xì)胞質(zhì)和細(xì)胞核中，破壞E-cadherin和β-catenin的結(jié)合，，抑制了E-cadherin和β-catenin介導(dǎo)的鈣離子依賴(lài)的細(xì)胞與細(xì)胞之間的粘附。 3．NRAGE能夠明顯地抑制Wnt信號(hào)通路。過(guò)表達(dá)NRAGE可誘導(dǎo)β-catenin發(fā)生O-乙酰氨基糖基化修飾，促進(jìn)β-catenin向細(xì)胞核內(nèi)轉(zhuǎn)移，增強(qiáng)β-catenin與DNA的結(jié)合能力。但由于糖基化的存在，β-catenin與Pygopus的結(jié)合受到抑制，進(jìn)一步抑制了Wnt信號(hào)通路。 4．Ror2蛋白能夠與Src激酶直接結(jié)合，激活Src介導(dǎo)的細(xì)胞的遷移，提高低轉(zhuǎn)移黑色素瘤細(xì)胞B16的轉(zhuǎn)移能力。NRAGE能夠同Src競(jìng)爭(zhēng)結(jié)合Rot2，抑制Ror2
[Abstract]:NRAGE (neurotrophin receptor-interacting MAGE homolog) is a member of the MAGE family. Most MAGE family proteins are expressed only in tumors, while NRAGE is expressed in many tissues in early development and adulthood, and NRAGE expression is low in some types of tumors. Recent studies have shown that NRAGE can play a different role by binding to a variety of proteins through its own hexapeptide repeat region WQXPXX and MAGE family conserved region (MHD): including nerve growth factor receptor (p75NTR). X chromosome linked apoptosis inhibitor protein (XIAP), UNC5H1, prion protein (PrPc) and other proteins to regulate cell proliferation and apoptosis; Binding to necdin,Msx2 protein can promote the differentiation of C2C12 cells into myocytes, and it can bind to Ror2 protein and regulate its distribution in cells. However, the study on the regulation of cell signaling pathway by NRAGE is not exact. The current study is limited to the effect of NRAGE on apoptosis and osteocyte differentiation. So we systematically studied the effect of NRAGE on cell apoptosis, adhesion, differentiation and related mechanisms. We found that 1.NRAGE can regulate p53 signaling pathway. NRAGE competes with Mdm2 in the N-terminal of non-phosphorylated p53 through its own WQXPXX and MAGE family conserved region (MHD). It inhibited the degradation of p53 by Mdm2, enhanced the stability of p53, promoted the expression of p21 ~ (CIP1/WAF1), inhibited the arrest of cell cycle during the transition between G0/G1 and G _ 2 / M, and promoted the apoptosis mediated by p53 under the stimulation of UV. 2.NRAGE can induce the transfer of 尾-catenin from cell membrane to cytoplasm and nucleus, destroy the binding of E-cadherin and 尾-catenin, and inhibit the adhesion between Ca ~ (2 +) -dependent cells mediated by E-cadherin and 尾 -catenin. 3.NRAGE can significantly inhibit Wnt signaling pathway. Overexpression of NRAGE could induce O-acetylglycosylation of 尾-catenin, promote the transfer of 尾-catenin into nucleus and enhance the binding ability of 尾-catenin to DNA. However, the binding of 尾-catenin to Pygopus was inhibited due to the presence of glycosylation, which further inhibited the Wnt signaling pathway. 4.Ror2 protein can directly bind to Src kinase, activate Src mediated cell migration, and enhance the metastatic ability of low metastasis melanoma cell B16. NRAGE can compete with Src to bind Rot2, to inhibit Ror2.
【學(xué)位授予單位】：南京師范大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2006
【分類(lèi)號(hào)】：R346

【引證文獻(xiàn)】

相關(guān)碩士學(xué)位論文 前1條

1 涂晨;Ror2調(diào)控腫瘤細(xì)胞遷移能力的實(shí)驗(yàn)研究[D];南京師范大學(xué);2007年

本文編號(hào)：2323290