Munkley Jennifer, Rajan Prabhakar, Lafferty Nicholas P, Dalgliesh Caroline, Jackson Robert M, Robson Craig N, Leung Hing Y, Elliott David J
Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne, United Kingdom.
Oncotarget. 2014 Jan 15;5(1):131-9. doi: 10.18632/oncotarget.1405.
TSC2 (Tuberous sclerosis complex 2) is an important tumour suppressor gene, mutations within which are linked to the development of tuberous sclerosis and implicated in multiple tumour types. TSC2 protein complexes with TSC1 and blocks the ability of the Rheb (Ras homolog enriched in brain) GTPase to activate mTOR (mammalian target of rapamycin), a crucial signal transducer which regulates protein synthesis and cell growth. Here, we report the characterisation of a novel isoform of TSC2 which is under direct control of the ligand-activated androgen receptor. TSC2 isoform A (TSC2A) is derived from an internal androgen-regulated alternative promoter and encodes a 508-amino acid cytoplasmic protein corresponding to the C-terminal region of full-length TSC2, lacking the interaction domain for TSC1 and containing an incomplete interaction domain required for Rheb inactivation. Expression of TSC2A is induced in response to androgens and full-length TSC2 is co-ordinately down-regulated, indicating an androgen-driven switch in TSC2 protein isoforms. In contrast to the well-characterised suppressive effect on cell proliferation of full-length TSC2 protein, both LNCaP and HEK293 cells over-expressing TSC2 isoform A proliferate more rapidly (measured by MTT assays) and have increased levels of cells in S-phase (measured by both Edu staining and FACS analysis). Our work indicates, for the first time, a novel role for this well-known tumour suppressor gene, which encodes an activator of cell proliferation in response to androgen stimulation.
TSC2（结节性硬化症复合物2）是一种重要的肿瘤抑制基因，其内部的突变与结节性硬化症的发生有关，并涉及多种肿瘤类型。TSC2蛋白与TSC1形成复合物，阻止Rheb（脑中富含的Ras同源物）GTP酶激活mTOR（雷帕霉素的哺乳动物靶标），mTOR是一种调节蛋白质合成和细胞生长的关键信号转导分子。在此，我们报道了一种受配体激活的雄激素受体直接调控的TSC2新亚型的特性。TSC2亚型A（TSC2A）源自一个内部雄激素调节的可变启动子，编码一种508个氨基酸的胞质蛋白，对应于全长TSC2的C末端区域，缺乏与TSC1的相互作用结构域，且含有Rheb失活所需的不完全相互作用结构域。TSC2A的表达在雄激素作用下被诱导，而全长TSC2则被协同下调，这表明雄激素驱动了TSC2蛋白亚型的转换。与全长TSC2蛋白对细胞增殖具有明确的抑制作用相反，过表达TSC2亚型A的LNCaP和HEK293细胞增殖更快（通过MTT分析测定），且S期细胞水平增加（通过Edu染色和FACS分析测定）。我们的工作首次表明了这个著名的肿瘤抑制基因的新作用，即它编码一种在雄激素刺激下的细胞增殖激活剂。
