三基序蛋白27的生理意义及其在肿瘤发生发展中的作用

Physiological Significance of TRIM27 and Its Role in Occurrence and Development of Tumors

三基序蛋白27(tripartite motif 27,TRIM27)是一种E3泛素连接酶,在细胞核、胞质溶胶和内体中均有分布,广泛存在于多种细胞中。TRIM27还具有转录抑制活性以及SUMO E3连接酶活性。TRIM27参与调控机体多种正常的生理过程:例如作为转录调控蛋白质促进减数分裂过程,与生殖过程密切相关;通过增强胱天蛋白酶3(cysteine-containing aspartate-specific protease-3,caspase-3)活性诱导正常细胞凋亡过程的发生;不仅可以抑制由IκB激酶(IkappaB kinase,IKK)家族成员介导的NF-κB的激活,还能通过泛素化降解NF-κB抑制剂Iκbα,进而参与NF-κB信号通路,在先天免疫中发挥重要调控作用;通过激活STAT3信号通路参与多种炎症疾病的发生。最新研究表明,TRIM27还参与了癌症进程关键信号通路,例如PI3K/AKT,Wnt/β-catenin等,从而促进非小细胞肺癌,结直肠癌和肝癌等多种常见癌症细胞的增殖、侵袭和转移能力,抑制它们凋亡过程的发生以及抑制卵巢癌细胞的细胞周期停滞。同时,TRIM27作为癌症干预的潜在靶点,还能与核因子Y(nuclear factor-Y,NF-Y)组成蛋白质复合物,而增强癌细胞对某些抗癌药物的耐药性。总之,TRIM27对于细胞的某些生命过程调控作用以及机制不同,甚至相反,这取决于细胞的类型以及所处的状态。本文将从TRIM27结构、生物学功能以及主要参与的信号通路出发,针对TRIM27发挥的生理意义和在肿瘤发生发展中起到的功能及调控机制等方面进行综述。

Tripartite motif 27(TRIM27)exists widely in a variety types of cell lines and is mainly distributed in the nucleus,cytosol and endosome.Besides its role as an E3 ubiquitin ligase,TRIM27 also showed transcriptional inhibitory activity and SUMO E3 ligase activity as well.Therefore TRIM27 is involved in various regular physiological processes of the organism.For example,TRIM27 promotes the meiosis process and is closely related to the reproductive process as a transcriptional regulatory protein.TRIM27 also induces normal cell apoptosis by enhancing the activity of cysteine-containing aspartate-specific protease-3(caspase-3).Moreover,TRIM27 can not only inhibit activation of NF-κB mediated by the Ikappa B kinase(IKK)family members,but also degrade the NF-κB inhibitor IκBαby ubiquitination,which in turn participates in the NF-κB signaling pathway and plays an important regulatory role in innate immunity.Furthermore,TRIM27 participates in the occurrence of various inflammatory diseases through activating the STAT3 signaling pathway.Additionally,several recent studies have also implicated that TRIM27 is closely related to the development of various tumors.Mechanically,TRIM27 promotes proliferation,invasion and metastasis of non-small cell lung cancer,colorectal cancer,liver cancer and other common cancer cells,inhibits the occurrence of their apoptosis and inhibits cell cycle arrest of ovarian cancer cells by participating in key signaling pathways of cancer,such as PI3K/AKT,Wnt/β-catenin,etc.Meanwhile,TRIM27,as a potential target of cancer intervention,can also form protein complexes with nuclear factor-Y(NF-Y)and increase the resistance of cancer cells to certain anticancer drugs.Altogether,TRIM27 has different or even opposite regulatory effects and mechanisms on some biological processes,which depends on the type and state of the cell.Through focusing on the recent findings of the structure,biological function,and signal transduction pathway of TRIM27,this review systematically summarizes its significance in both physiological conditions and tumorigenesis.