Perl Andras
Division of Rheumatology, Department of Medicine State University of New York, Upstate Medical University, College of Medicine, Syracuse, New York.
Division of Rheumatology, Department of Microbiology and Immunology, State University of New York, Upstate Medical University, College of Medicine, Syracuse, New York.
Ann N Y Acad Sci. 2015 Jun;1346(1):33-44. doi: 10.1111/nyas.12756. Epub 2015 Apr 23.
The mechanistic target of rapamycin (mTOR) is a ubiquitous serine/threonine kinase, which plays pivotal roles in integrating growth signals on a cellular level. To support proliferation and survival under stress, two interacting complexes that harbor mTOR, mTORC1 and mTORC2, promote the transcription of genes involved in carbohydrate metabolism and lipogenesis, enhance protein translation, and inhibit autophagy. Although rapamycin was originally developed as an inhibitor of T cell proliferation for preventing organ transplant rejection, its molecular target, mTOR, has been subsequently identified as a central regulator of metabolic cues that drive lineage specification in the immune system. Owing to oxidative stress, the activation of mTORC1 has emerged as a central pathway for the pathogenesis of systemic lupus erythematosus and other autoimmune diseases. Paradoxically, mTORC1 has also been identified as a mediator of the Warburg effect that allows cell survival under hypoxia. Rapamycin and new classes of mTOR inhibitors are being developed to block not only transplant rejection and autoimmunity but also to treat obesity and various forms of cancer. Through preventing these diseases, personalized mTOR blockade holds promise to extend life span.
雷帕霉素的作用机制靶点(mTOR)是一种普遍存在的丝氨酸/苏氨酸激酶,在细胞水平整合生长信号方面发挥关键作用。为了在应激状态下支持细胞增殖和存活,包含mTOR的两种相互作用复合物,即mTORC1和mTORC2,可促进参与碳水化合物代谢和脂肪生成的基因转录,增强蛋白质翻译,并抑制自噬。尽管雷帕霉素最初是作为一种T细胞增殖抑制剂开发出来用于预防器官移植排斥反应的,但其分子靶点mTOR随后被确定为驱动免疫系统谱系分化的代谢信号的核心调节因子。由于氧化应激,mTORC1的激活已成为系统性红斑狼疮和其他自身免疫性疾病发病机制的核心途径。矛盾的是,mTORC1也被确定为瓦伯格效应的介导因子,该效应可使细胞在缺氧条件下存活。目前正在开发雷帕霉素和新型mTOR抑制剂,不仅用于阻断移植排斥反应和自身免疫,还用于治疗肥胖症和各种癌症。通过预防这些疾病,个性化的mTOR阻断有望延长寿命。