摘要:来自复旦大学附属中山医院的研究人员发现泛素羧基末端水解酶37(UCH37)在肝癌组织中呈高表达,并通过查阅大量文献,对泛素羧基末端水解酶家族(UCHs)在恶性肿瘤发生、发展及预后中的作用进行了综述。相关研究成果公布在国际核心期刊《生物化学与生物物理学学报》(Biochimica et Biophysica Acta-Reviews on Cancer)上(影响因子11.685)。
这项研究由复旦大学附属中山医院消化科主任沈锡中教授课题组完成,沈锡中教授早年师从我国著名消化病专家江绍基院士、萧树东教授,1995年获医学博士学位,之后曾在香港大学医学院进修胃肠病。目前主持863课题、国家自然科学基金等多项研究工作。
肝癌是影响人类健康最常见的恶性肿瘤之一,但对肝癌发病机制的研究尚处于初级阶段,因此,探索肝癌发病的分子机制对于攻克肝癌具有重要意义。
已知研究表明,泛素是一个由76个氨基酸组成的高度保守的小分子蛋白,依赖泛素的蛋白质降解途径可以选择性地降解细胞内的蛋白质,是一条重要的非溶酶体蛋白降解途径,该途径的发现获得了2004年诺贝尔化学奖。
随着研究的深入,研究人员发现蛋白质泛素化调节是一个可逆的过程。细胞内存在多种去泛素化酶,该酶能催化水解泛素羧基末端多肽链连接,起到去泛素化的作用,对蛋白质降解进行反向调节,从而影响蛋白质和细胞的功能。细胞内蛋白质泛素化和去泛素化调节的动态平衡参与了细胞生命活动的调节,包括细胞的代谢、分化、增殖等,还能选择性地降解或稳定癌基因、抑癌基因的产物、激活物或抑制物、凋亡调控蛋白等,达到调控细胞突变和肿瘤发生的目的。
沈锡中教授等对一种去泛素化酶――泛素羧基末端水解酶家族(UCHs) 在恶性肿瘤发生、发展及预后中的作用进行了综述。该综述首次从家族成员、生物学功能、参与的信号通路等方面对UCH家族进行了全面、深入的阐述。
这一综述明确了UCH家族在恶性肿瘤中的作用,同时指出对其在恶性肿瘤中分子机制方面的研究尚处于起步阶段,并提出了许多有价值的建议和假设,为该领域的深入研究指明了方向。
生物探索推荐英文论文摘要:
The potential role of ubiquitin c-terminal hydrolases in oncogenesis.
Abstract
Deubiquitinating enzymes (DUBs), capable of removing ubiquitin (Ub) from protein substrates, are involved in numerous biological processes. The ubiquitin C-terminal hydrolases (UCHs) subfamily of DUBs consists of four members: UCH-L1, UCH-L3, UCH37 and BRCA1-associated protein-1 (BAP1). UCH-L1 possesses deubiquitinating activity and dimerization-dependent ubiquitin ligase activity, and functions as a mono-ubiquitin stabilizer; UCH-L3 does both deubiquitinating and deneddylating activity, except dimerization or ligase activity, and unlike UCH-L1, can interact with Lys48-linked Ub dimers to protect it from degradation and in the meanwhile to inhibit its hydrolase activity; UCH37 is responsible for the deubiquitinating activity in the 19S proteasome regulatory complex, and as indicated by the recent study, UCH37 is also associated with the human Ino80 chromatin-remodeling complex (hINO80) in the nucleus and can be activated via transient association of 19S regulatory particle- or proteasome-bound hRpn13 with hINO80; BAP1, binding to the wild-type BRCA1 RING finger domain, is regarded as a tumor suppressor, but for such suppressing activity, as demonstrated otherwise, both deubiquitinating activity and nucleus localization are required. There is growing evidence that UCH enzymes and human malignancies are closely correlated. Previous studies have shown that UCH enzymes play a crucial role in some signalings and cell-cycle regulation. In this review, we provided an insight into the relation between UCH enzymes and oncogenesis.
