Thomas Janice D, Zhang Yan-Jie, Wei Yue-Hua, Cho Jun-Hung, Morris Laura E, Wang Hui-Yun, Zheng X F Steven
Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08903, USA; Department of Pharmacology, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, 675 Hoes Lane, Piscataway, NJ 08854, USA.
Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08903, USA; Department of Pharmacology, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, 675 Hoes Lane, Piscataway, NJ 08854, USA; Department of Gastroenterology, No. 3 People's Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 201900, China.
Cancer Cell. 2014 Nov 10;26(5):754-69. doi: 10.1016/j.ccell.2014.09.008. Epub 2014 Oct 23.
Amino acid (AA) is a potent mitogen that controls growth and metabolism. Here we describe the identification of Rab1 as a conserved regulator of AA signaling to mTORC1. AA stimulates Rab1A GTP binding and interaction with mTORC1 and Rheb-mTORC1 interaction in the Golgi. Rab1A overexpression promotes mTORC1 signaling and oncogenic growth in an AA- and mTORC1-dependent manner. Conversely, Rab1A knockdown selectively attenuates oncogenic growth of Rab1-overexpressing cancer cells. Moreover, Rab1A is overexpressed in colorectal cancer (CRC), which is correlated with elevated mTORC1 signaling, tumor invasion, progression, and poor prognosis. Our results demonstrate that Rab1 is an mTORC1 activator and an oncogene and that hyperactive AA signaling through Rab1A overexpression drives oncogenesis and renders cancer cells prone to mTORC1-targeted therapy.
氨基酸（AA）是一种控制生长和代谢的强效有丝分裂原。在此，我们描述了Rab1作为AA信号传导至mTORC1的保守调节因子的鉴定。AA刺激Rab1A的GTP结合以及在高尔基体中与mTORC1的相互作用和Rheb-mTORC1相互作用。Rab1A的过表达以AA和mTORC1依赖的方式促进mTORC1信号传导和致癌生长。相反，Rab1A的敲低选择性地减弱Rab1过表达癌细胞的致癌生长。此外，Rab1A在结直肠癌（CRC）中过表达，这与mTORC1信号传导升高、肿瘤侵袭、进展及不良预后相关。我们的结果表明，Rab1是一种mTORC1激活剂和癌基因，并且通过Rab1A过表达的过度活跃的AA信号传导驱动肿瘤发生，并使癌细胞易于接受mTORC1靶向治疗。
