Qin Y, Deng Y, Ricketts C J, Srikantan S, Wang E, Maher E R, Dahia P L M
Department of Medicine.
Hum Mol Genet. 2014 May 1;23(9):2428-39. doi: 10.1093/hmg/ddt638. Epub 2013 Dec 13.
TMEM127 is an endosome-associated tumor suppressor gene in pheochromocytomas, neuroendocrine tumors that can co-occur with renal cell carcinomas (RCCs). TMEM127 loss leads to increased mTOR signaling. However, the spectrum of tumors with TMEM127 mutation and how TMEM127 and mTOR interact in tumorigenesis remains unknown. Here, we report that germline TMEM127 mutations occur in RCCs and that some mutant proteins, unlike wild-type (WT) TMEM127, fail to cooperate with activated early endosomal GTPase, Rab5, to inhibit mTOR signaling. Tmem127-null mouse embryonic fibroblasts (MEFs) are deficient in generating early-to-late hybrid endosomes upon constitutive Rab5 activation, a defect rescued by WT, but not mutant, TMEM127. This endosomal dysfunction results in diminished mTOR colocalization with Rab5-positive vesicles. Conversely, active, lysosomal-bound mTOR is increased in Tmem127-null MEFs, which also display enhanced lysosomal biogenesis. Our data map the tumor-suppressive properties of TMEM127 to modulation of mTOR function in the endolysosome, a feature that may contribute to both pheochromocytoma and RCC pathogenesis.
TMEM127是一种与内体相关的肿瘤抑制基因，存在于嗜铬细胞瘤中，嗜铬细胞瘤是一种可与肾细胞癌（RCC）同时发生的神经内分泌肿瘤。TMEM127缺失会导致mTOR信号增强。然而，TMEM127突变的肿瘤谱以及TMEM127与mTOR在肿瘤发生过程中如何相互作用仍不清楚。在此，我们报告种系TMEM127突变发生在肾细胞癌中，并且一些突变蛋白与野生型（WT）TMEM127不同，无法与活化的早期内体GTP酶Rab5协同抑制mTOR信号。Tmem127基因敲除的小鼠胚胎成纤维细胞（MEF）在组成型Rab5激活后生成早期到晚期混合内体存在缺陷，野生型而非突变型TMEM127可挽救这一缺陷。这种内体功能障碍导致mTOR与Rab5阳性囊泡的共定位减少。相反，在Tmem127基因敲除的MEF中，活跃的、与溶酶体结合的mTOR增加，这些细胞还表现出溶酶体生物合成增强。我们的数据将TMEM127的肿瘤抑制特性映射到内溶酶体中mTOR功能的调节上，这一特征可能对嗜铬细胞瘤和肾细胞癌的发病机制都有贡献。
