SET结合蛋白调控SET表达的机制及意义

SET Expression was Regulated by the SET-related Proteins

Set(patient SE translocation)在1992年以set-can融合基因的形式为人们所知,其参与调控DNA复制、核小体装配、组蛋白修饰、DNA转录和细胞凋亡等多个生物过程,并作为原癌基因促肿瘤发生。SET蛋白在多种组织细胞中广泛表达;在肾上腺及性腺的类固醇合成细胞中,能够通过抑制蛋白磷酸酶2(PP2A),正向调控细胞色素P450 17α羟化酶(P450c17)的裂解酶活性,最终促进雄激素的合成。SET蛋白的丝氨酸(Ser)位点磷酸化介导SET的胞质聚集,并增强SET与下游蛋白的结合力,在阿尔茨海默病(AD)、肿瘤发生等多种病理过程中发挥作用。现已发现的SET结合蛋白,功能涉及代谢、信号传导、核酸转录及翻译等多种生物学过程。已有很多研究着眼于SET结合蛋白,从而发现了SET新的生物学功能。多种肿瘤抑制剂通过与SET结合使SET蛋白失活,提高PP2A活性,最终抑制肺癌、乳腺癌等多种肿瘤的生长和转移。综述SET蛋白结构、磷酸化及SET相互作用蛋白,并总结以SET为靶向标记的抗肿瘤药物。

Set was firstly described as a part of the set-can fusion gene associated with acute undifferentiated leukemia in 1992. The Set protein（SET） expressed widely in human tissues is a multifunctional protein in regulating DNA replication, nucleosome assembly, histone modification, gene transcription and cell apoptosis. It participates in the regulation of testosterone biosynthesis by inhibiting PP2 A activity and further activating the lyase activity of P450c17 in those steroidogenetic cells in gonadal system and adrenal gland.Phosphorylation of ser causes cytoplasmic detention of SET which aggravates the protein-protein interaction and then triggers Alzheimer′ s disease（AD） pathogenesis and oncogenesis. The SET-binding proteins refer to many major functional groups like metabolism, signal transduction, transcription and translation. Study on the SET-binding proteins revealed new SET functions. Many kinds of bioactive tumor suppressors inhibit SET activation by binding PP2 A and activating PP2 A function. SET suppressor could be a beneficial approach to prevent cancer growth and metastasis, including prostate cancer, lung cancer and so on. This review will focus on the structure,phosphorylation regulation, regulatory proteins and binding proteins of SET, and summarize the potential antineoplastic drugs targeted on SET.