NRAGE抑制细胞生长、粘附和迁移分子机理的研究
发布时间：2018-11-10 18:42
【摘要】：NRAGE(neurotrophin receptor-interacting MAGE homolog)是MAGE(黑色素瘤抗原)家族的一员。大部分MAGE家族的蛋白仅在肿瘤中表达，而NRAGE却在发育早期和成年期的许多组织中都有表达，在某些类型的肿瘤中NRAGE的表达量较低。近来研究表明，NRAGE能够通过自身的六肽重复区WQXPXX和MAGE家族保守区(MHD)同多种蛋白结合，发挥不同的作用：包括与神经生长因子受体(p75NTR)、X染色体相连的凋亡抑制蛋白(XIAP)、UNC5H1、朊病毒蛋白(PrPc)等蛋白结合，调节细胞的增殖和凋亡；与necdin、Msx2蛋白结合促进C2C12细胞向肌细胞的分化，同时可以与Ror2蛋白结合，调节自身在细胞内的分布。但有关NRAGE调控细胞信号通路的研究并不确切，目前的研究仅局限于NRAGE对细胞凋亡与骨细胞分化的作用。于是我们系统地研究了NRAGE对细胞凋亡、粘附、分化的作用及相关机制。我们研究发现： 1．NRAGE能够调控p53信号通路。NRAGE通过自身的六肽重复区WQXPXX和MAGE家族保守区(MHD)与Mdm2竞争直接结合于非磷酸化的p53的N端，抑制Mdm2对p53的泛素化降解，提高p53的稳定性，促进p53下游基因p21~(CIP1/WAF1)的表达，抑制细胞周期在G0／G1和G2／M期转换时发生阻滞，促进在UV刺激下由p53介导的细胞凋亡。 2．NRAGE能够促使β-catenin由细胞膜分布转移到细胞质和细胞核中，破坏E-cadherin和β-catenin的结合，，抑制了E-cadherin和β-catenin介导的钙离子依赖的细胞与细胞之间的粘附。 3．NRAGE能够明显地抑制Wnt信号通路。过表达NRAGE可诱导β-catenin发生O-乙酰氨基糖基化修饰，促进β-catenin向细胞核内转移，增强β-catenin与DNA的结合能力。但由于糖基化的存在，β-catenin与Pygopus的结合受到抑制，进一步抑制了Wnt信号通路。 4．Ror2蛋白能够与Src激酶直接结合，激活Src介导的细胞的迁移，提高低转移黑色素瘤细胞B16的转移能力。NRAGE能够同Src竞争结合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.
【学位授予单位】：南京师范大学
【学位级别】：博士
【学位授予年份】：2006
【分类号】：R346
本文编号：2323290
[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.
【学位授予单位】：南京师范大学
【学位级别】：博士
【学位授予年份】：2006
【分类号】：R346
【引证文献】
相关硕士学位论文 前1条
1 涂晨;Ror2调控肿瘤细胞迁移能力的实验研究[D];南京师范大学;2007年
本文编号：2323290
本文链接：https://www.wllwen.com/yixuelunwen/binglixuelunwen/2323290.html
最近更新
教材专著
