Regulation of YAP by mTOR and autophagy reveals a therapeutic target of tuberous sclerosis complex.
Regulation of YAP by mTOR and autophagy reveals a therapeutic target of tuberous sclerosis complex.
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DOI：
10.1084/jem.20140341
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发表时间：
2014-10-20
期刊：
影响因子：
--
通讯作者：
Pende M
中科院分区：
文献类型：
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作者：
Liang N;Zhang C;Dill P;Panasyuk G;Pion D;Koka V;Gallazzini M;Olson EN;Lam H;Henske EP;Dong Z;Apte U;Pallet N;Johnson RL;Terzi F;Kwiatkowski DJ;Scoazec JY;Martignoni G;Pende M
Liang等人发现肿瘤抑制因子TSC 1和TSC 2（其中的缺陷是遗传疾病多发性硬化症复合体（TSC）的基础）驱动转录激活因子雅普的mTOR依赖性自噬体破坏。阻断雅普可抑制TSC 1/2缺陷型人类细胞的异常增殖，并逆转嵌合型Tsc 1突变小鼠的TSC样疾病症状。遗传学研究表明，结节性硬化症复合体（TSC）1-TSC 2-哺乳动物雷帕霉素靶蛋白（mTOR）和Hippo-Yes-相关蛋白1（雅普）途径是器官大小的主要调节剂，其通常参与肿瘤发生。这些信号转导通路之间的串扰在协调环境线索，如营养状况和机械约束，是至关重要的组织生长。mTOR是否以及如何调节雅普仍然是一个谜。在这里，我们描述了一种新的TSC小鼠模型，该模型发展成与TSC患者的人血管周围上皮样细胞肿瘤（PEComas）相似的肾间质病变。我们发现雅普在小鼠和人PEComa中被mTOR上调。雅普抑制钝化了培养物和嵌合Tsc 1突变小鼠中TSC 1-TSC 2缺陷细胞的异常增殖并诱导其凋亡。我们进一步描述了雅普在TSC 1/TSC 2缺陷细胞中的积累是由于自噬体/溶酶体系统对蛋白质的降解受损。因此，mTOR和自噬对雅普的调节是一种新的生长控制机制，使雅普活性与生长允许条件下的营养可用性相匹配。雅普可能作为TSC和其他mTOR活性失调疾病的潜在治疗靶点。
Liang et al. find that the tumor suppressors TSC1 and TSC2, defects in which underlie the genetic disease Tuberous Sclerosis Complex (TSC), drive the mTOR-dependent autophagosomal destruction of the transcriptional activator YAP. Blocking YAP inhibited the abnormal proliferation of TSC1/2-deficient human cells and reversed TSC-like disease symptoms in mosaic Tsc1 mutant mice. Genetic studies have shown that the tuberous sclerosis complex (TSC) 1–TSC2–mammalian target of Rapamycin (mTOR) and the Hippo–Yes-associated protein 1 (YAP) pathways are master regulators of organ size, which are often involved in tumorigenesis. The crosstalk between these signal transduction pathways in coordinating environmental cues, such as nutritional status and mechanical constraints, is crucial for tissue growth. Whether and how mTOR regulates YAP remains elusive. Here we describe a novel mouse model of TSC which develops renal mesenchymal lesions recapitulating human perivascular epithelioid cell tumors (PEComas) from patients with TSC. We identify that YAP is up-regulated by mTOR in mouse and human PEComas. YAP inhibition blunts abnormal proliferation and induces apoptosis of TSC1–TSC2-deficient cells, both in culture and in mosaic Tsc1 mutant mice. We further delineate that YAP accumulation in TSC1/TSC2-deficient cells is due to impaired degradation of the protein by the autophagosome/lysosome system. Thus, the regulation of YAP by mTOR and autophagy is a novel mechanism of growth control, matching YAP activity with nutrient availability under growth-permissive conditions. YAP may serve as a potential therapeutic target for TSC and other diseases with dysregulated mTOR activity.
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影响因子：
11.1
作者：
He C;Klionsky DJ
通讯作者：
Klionsky DJ
影响因子：
168.9
作者：
Bissler, John J.;Kingswood, J. Christopher;Budde, Klemens
通讯作者：
Budde, Klemens
影响因子：
64.5
作者：
Dong, Jixin;Feldmann, Georg;Pan, Duojia
通讯作者：
Pan, Duojia
DOI：
10.1083/jcb.200412022
发表时间：
2005-05-09
期刊：
The Journal of cell biology
影响因子：
--
作者：
Komatsu M;Waguri S;Ueno T;Iwata J;Murata S;Tanida I;Ezaki J;Mizushima N;Ohsumi Y;Uchiyama Y;Kominami E;Tanaka K;Chiba T
通讯作者：
Chiba T
影响因子：
21.3
作者：
通讯作者：
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