The Spectrum of Renal "TFEopathies": Flipping the mTOR Switch in Renal Tumorigenesis.

IF 5.3 2区 医学 Q1 PHYSIOLOGY
Physiology Pub Date : 2024-11-01 Epub Date: 2024-07-16 DOI:10.1152/physiol.00026.2024
Nicola Alesi, Kaushal Asrani, Tamara L Lotan, Elizabeth P Henske
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引用次数: 0

Abstract

The mammalian target of Rapamycin complex 1 (mTORC1) is a serine/threonine kinase that couples nutrient and growth factor signaling to the cellular control of metabolism and plays a fundamental role in aberrant proliferation in cancer. mTORC1 has previously been considered an "on/off" switch, capable of phosphorylating the entire pool of its substrates when activated. However, recent studies have indicated that mTORC1 may be active toward its canonical substrates, eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1) and S6 kinase (S6K), involved in mRNA translation and protein synthesis, and inactive toward TFEB and TFE3, transcription factors involved in the regulation of lysosome biogenesis, in several pathological contexts. Among these conditions are Birt-Hogg-Dubé syndrome (BHD) and, recently, tuberous sclerosis complex (TSC). Furthermore, increased TFEB and TFE3 nuclear localization in these syndromes, and in translocation renal cell carcinomas (tRCC), drives mTORC1 activity toward the canonical substrates, through the transcriptional activation of the Rag GTPases, thereby positioning TFEB and TFE3 upstream of mTORC1 activity toward 4EBP1 and S6K. The expanding importance of TFEB and TFE3 in the pathogenesis of these renal diseases warrants a novel clinical grouping that we term "TFEopathies." Currently, there are no therapeutic options directly targeting TFEB and TFE3, which represents a challenging and critically required avenue for cancer research.

TFEopathies "谱系--翻转肾脏肿瘤发生过程中的 mTOR 开关。
哺乳动物雷帕霉素靶标复合体 1(mTORC1)是一种丝氨酸苏氨酸激酶,它将营养物质和生长因子信号传导与细胞对新陈代谢的控制结合起来,并在癌症的异常增殖中发挥着重要作用。然而,最近的研究表明,在一些病理情况下,mTORC1 对其典型底物 4EBP1 和 S6K(参与 mRNA 翻译和蛋白质合成)可能具有活性,而对 TFEB 和 TFE3(参与溶酶体生物生成调控的转录因子)则不具有活性。这些病症包括 Birt Hogg Dube(BHD)和最近的结节性硬化综合症(TSC)。此外,在这些综合征以及易位肾细胞癌(tRCC)中,TFEB 和 TFE3 的超活化通过 Rag GTP 酶的转录激活,促使 mTORC1 的活性朝向规范底物,从而将 TFEB 和 TFE3 定位在 mTORC1 活性的上游,朝向 4EBP1 和 S6K。TFEB 和 TFE3 在这些肾脏疾病发病机制中的重要性不断扩大,因此我们将其称为 "TFEopathies",这是一个新的临床分组。目前,还没有直接针对 TFEB 和 TFE3 的治疗方案,这是癌症研究中极具挑战性和亟需的途径。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Physiology
Physiology 医学-生理学
CiteScore
14.50
自引率
0.00%
发文量
37
期刊介绍: Physiology journal features meticulously crafted review articles penned by esteemed leaders in their respective fields. These articles undergo rigorous peer review and showcase the forefront of cutting-edge advances across various domains of physiology. Our Editorial Board, comprised of distinguished leaders in the broad spectrum of physiology, convenes annually to deliberate and recommend pioneering topics for review articles, as well as select the most suitable scientists to author these articles. Join us in exploring the forefront of physiological research and innovation.
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