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中科院E3泛素连接酶RNF126调控肿瘤细胞增殖机理的最新发现

标签: 泛素化
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摘要 : 中国科学院昆明动物研究所陈策实研究员课题组通过对含555个泛素连接酶小RNA文库的筛选,鉴定出一个新的具有癌蛋白性质的含RING指结构的E3泛素连接酶RNF126。抑制RNF126显著抑制多种癌细胞增殖,导致细胞周期捕获在G1期,通过蛋白芯片扫描,研究者发现该泛素连接酶通过使其底物-细胞周期蛋白激酶抑制剂p21泛素化,导致p21蛋白降解,从而促进细胞周期从G1进入S期,并促进乳腺癌
蛋白泛素化在维持细胞稳定性和调控多种生物学过程(包括细胞周期)中起着至关重要的作用,其系统功能紊乱与多种肿瘤(如乳腺癌等)产生和发展关系密切。蛋白泛素化过程由三种酶依次催化完成,包括泛素激活酶(E1)、泛素连接酶(E2)和泛素连接酶(E3)。E3泛素连接酶决定了泛素化底物的特异性,大量研究表明其可能是肿瘤靶向治疗的有效靶标。但是,目前大量的E3泛素连接酶的功能还不清楚。鉴定E3泛素连接酶所修饰的底物蛋白,以及阐明它们与人类疾病(如恶性肿瘤)的关系将是该领域需要解决的重要课题。 中国科学院昆明动物研究所陈策实研究员课题组通过对含555个泛素连接酶小RNA文库的筛选,鉴定出一个新的具有癌蛋白性质的含RING指结构的E3泛素连接酶RNF126。抑制RNF126显著抑制多种癌细胞增殖,导致细胞周期捕获在G1期,通过蛋白芯片扫描,研究者发现该泛素连接酶通过使其底物-细胞周期蛋白激酶抑制剂p21泛素化,导致p21蛋白降解,从而促进细胞周期从G1进入S期,并促进乳腺癌和前列腺癌细胞在体外以及体内的生长。 这是国际上第一篇完整报道RNF126功能和机制的科研论文,所以该项研究具有高原创性以及较大的应用潜力,研究结果可能用于乳腺癌以及前列腺癌的早期诊断、预测病人治疗后的结果以及开发新的靶向治疗药物。 该研究发表于10月1日发表在Cancer Research上。 该研究项目得到了中国科学院干细胞先导专项、云南省高端科技人才项目、国家自然科学基金等项目的资助。 原文摘要: E3 ubiquitin ligase RNF126 promotes cancer cell proliferation by targeting the tumor suppressor p21 for ubiquitin-mediated degradation. To identify novel oncogenic E3 ubiquitin ligases as anti-cancer targets, we screened an E3 ubiquitin ligase siRNA library containing siRNA pools against 555 individual E3s using the SRB assay in the MDA-MB-231 breast cancer cell line and the PC3 prostate cancer cell line. RNF126 was identified and validated as a candidate from this screening. Knockdown of RNF126 dramatically decreased cell viability in these cancer cell lines. Consistently, RNF126 knockdown delayed cell cycle G1/S progression and decreased cell proliferation. Using protein array analysis we found that RNF126 silencing increased cell cycle dependent kinase inhibitor p21cip protein levels in both MDA-MB-231 and PC3. Knockdown of RNF126 stabilized the p21 protein rather than increased p21 mRNA levels. We demonstrated that RNF126 interacts with p21 and RNF126 over-expression increased p21 protein ubiquitination in an E3 ligase activity-dependent manner. RNF126 knockdown induced loss of cell viability in MDA-MB-231 and PC-3 can be partially rescued by depletion of p21. RNF126 stable knockdown in PC3 inhibited tumor growth in SCID mice. Finally, we found that RNF126 is highly expressed in a subset of breast cancer cell lines and negatively correlated with p21 expression levels. These findings suggest that RNF126 promotes cancer cell proliferation by targeting p21 for ubiquitin-mediated degradation. RNF126 could be a novel therapeutic target in breast and prostate cancers. 作者:青岚 点击:
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