The mTOR signalling pathway in human cancer.
The mTOR signalling pathway in human cancer.
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DOI：
10.3390/ijms13021886
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发表时间：
2012
影响因子：
5.6
通讯作者：
Soares P
中科院分区：
文献类型：
--
作者：
Pópulo H;Lopes JM;Soares P
保守的丝氨酸/苏氨酸激酶mTOR（雷帕霉素的哺乳动物靶标）是PI 3 K/AKT通路的下游效应子，形成两种不同的多蛋白复合物：mTORC 1和mTORC 2。mTORC 1对雷帕霉素敏感，激活S6 K1和4 EBP 1，它们参与mRNA翻译。它被多种刺激激活，如生长因子，营养素，能量和应激信号，以及基本信号传导途径，如PI 3 K，MAPK和AMPK，以控制细胞生长，增殖和存活。mTORC 2被认为对雷帕霉素具有抗性，并且通常对营养物和能量信号不敏感。它激活PKC-α和AKT并调节肌动蛋白细胞骨架。在许多类型的癌症中，特别是在黑色素瘤中，已经报道了mTOR途径的多个元件的失调（PI 3 K扩增/突变、PTEN功能丧失、AKT过表达以及S6 K1、4 EBP 1和eIF 4 E过表达），其中据报道mTOR途径的主要组分的改变对肿瘤进展具有显著影响。因此，mTOR是一种有吸引力的治疗靶点，并且mTOR抑制剂，包括雷帕霉素类似物地福莫司、依维莫司和替西罗莫司，被提交用于单独或与其他途径的抑制剂组合治疗多种癌症的临床试验。重要的是，替西罗莫司和依维莫司最近被FDA批准用于治疗肾细胞癌、PNET和巨细胞星形细胞瘤。抑制mTOR激酶活性的小分子和双重PI 3 K-mTOR抑制剂也正在开发中。在这篇综述中，我们的目的是调查相关的研究，信号传导的分子机制，包括上游激活和下游效应，以及mTOR在癌症中的作用，主要是在黑色素瘤。
The conserved serine/threonine kinase mTOR (the mammalian target of rapamycin), a downstream effector of the PI3K/AKT pathway, forms two distinct multiprotein complexes: mTORC1 and mTORC2. mTORC1 is sensitive to rapamycin, activates S6K1 and 4EBP1, which are involved in mRNA translation. It is activated by diverse stimuli, such as growth factors, nutrients, energy and stress signals, and essential signalling pathways, such as PI3K, MAPK and AMPK, in order to control cell growth, proliferation and survival. mTORC2 is considered resistant to rapamycin and is generally insensitive to nutrients and energy signals. It activates PKC-α and AKT and regulates the actin cytoskeleton. Deregulation of multiple elements of the mTOR pathway (PI3K amplification/mutation, PTEN loss of function, AKT overexpression, and S6K1, 4EBP1 and eIF4E overexpression) has been reported in many types of cancers, particularly in melanoma, where alterations in major components of the mTOR pathway were reported to have significant effects on tumour progression. Therefore, mTOR is an appealing therapeutic target and mTOR inhibitors, including the rapamycin analogues deforolimus, everolimus and temsirolimus, are submitted to clinical trials for treating multiple cancers, alone or in combination with inhibitors of other pathways. Importantly, temsirolimus and everolimus were recently approved by the FDA for the treatment of renal cell carcinoma, PNET and giant cell astrocytoma. Small molecules that inhibit mTOR kinase activity and dual PI3K-mTOR inhibitors are also being developed. In this review, we aim to survey relevant research, the molecular mechanisms of signalling, including upstream activation and downstream effectors, and the role of mTOR in cancer, mainly in melanoma.
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雷帕霉素在I期试验中针对复发性PTEN缺陷型胶质母细胞瘤患者的抗肿瘤活性。
影响因子：
15.8
作者：
Cloughesy, Tim F.;Yoshimoto, Koji;Nghiemphu, Phioanh;Brown, Kevin;Dang, Julie;Zhu, Shaojun;Hsueh, Teli;Chen, Yinan;Wang, Wei;Youngkin, David;Liau, Linda;Martin, Neil;Becker, Don;Bergsneider, Marvin;Lai, Albert;Green, Richard;Oglesby, Tom;Koleto, Michael;Trent, Jeff;Horvath, Steve;Mischel, Paul S.;Mellinghoff, Ingo K.;Sawyers, Charles L.
通讯作者：
Sawyers, Charles L.
DOI：
10.1126/science.1173635
发表时间：
2009-07-10
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Colman RJ;Anderson RM;Johnson SC;Kastman EK;Kosmatka KJ;Beasley TM;Allison DB;Cruzen C;Simmons HA;Kemnitz JW;Weindruch R
通讯作者：
Weindruch R
影响因子：
8.8
作者：
Coleman, L. J.;Peter, M. B.;Teall, T. J.;Brannan, R. A.;Hanby, A. M.;Honarpisheh, H.;Shaaban, A. M.;Smith, L.;Speirs, V.;Verghese, E. T.;McElwaine, J. N.;Hughes, T. A.
通讯作者：
Hughes, T. A.
DOI：
10.1073/pnas.0409143102
发表时间：
2005-01-18
影响因子：
11.1
作者：
Ballif, BA;Roux, PP;Gygi, SP
通讯作者：
Gygi, SP
影响因子：
7.7
作者：
Choi, JH;Bertram, PG;Zheng, XFS
通讯作者：
Zheng, XFS