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Dennis MD Baum JI Kimball SR Jefferson LS 《The Journal of biological chemistry》2011,286(10):8287-8296
In this study, we explored the coordinate regulation of mTORC1 by insulin and amino acids. Rat livers were perfused with medium containing various concentrations of insulin and/or amino acids. At fasting (1×) or 2× (2×AA) concentrations of amino acids, insulin maximally stimulated Akt phosphorylation but had no effect on global rates of protein synthesis. In the absence of insulin, 4×AA produced a moderate stimulation of protein synthesis and activation of mTORC1. The combination of 4×AA and insulin produced a maximal stimulation of protein synthesis and activation of mTORC1. These effects were accompanied by decreases in raptor and PRAS40 and an increase in RagC associated with mTOR (mammalian target of rapamycin). The studies were extended to a cell culture model in which mTORC1 activity was repressed by deprivation of leucine and serum, and resupplementation with the amino acid and insulin acted in an additive manner to restore mTORC1 activation. In deprived cells, mTORC1 was activated by expressing either constitutively active (ca) Rheb or a caRagB·caRagC complex, and coexpression of the constructs had an additive effect. Notably, resupplementation with leucine in cells expressing caRheb or with insulin in cells expressing the caRagB·caRagC complex was as effective as resupplementation with both leucine and insulin in non-transfected cells. Moreover, changes in mTORC1 activity correlated directly with altered association of mTOR with RagB/RagC, Rheb, raptor, and PRAS40. Overall, the results suggest that amino acids signal through the Rag complex and insulin through Rheb to achieve coordinate activation of mTORC1. 相似文献
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Qin Xia Hongfeng Wang Zongbing Hao Cheng Fu Qingsong Hu Feng Gao Haigang Ren Dong Chen Junhai Han Zheng Ying Guanghui Wang 《The EMBO journal》2016,35(2):121-142
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that is characterized by selective loss of motor neurons in brain and spinal cord. TAR DNA‐binding protein 43 (TDP‐43) was identified as a major component of disease pathogenesis in ALS, frontotemporal lobar degeneration (FTLD), and other neurodegenerative disease. Despite the fact that TDP‐43 is a multi‐functional protein involved in RNA processing and a large number of TDP‐43 RNA targets have been discovered, the initial toxic effect and the pathogenic mechanism underlying TDP‐43‐linked neurodegeneration remain elusive. In this study, we found that loss of TDP‐43 strongly induced a nuclear translocation of TFEB, the master regulator of lysosomal biogenesis and autophagy, through targeting the mTORC1 key component raptor. This regulation in turn enhanced global gene expressions in the autophagy–lysosome pathway (ALP) and increased autophagosomal and lysosomal biogenesis. However, loss of TDP‐43 also impaired the fusion of autophagosomes with lysosomes through dynactin 1 downregulation, leading to accumulation of immature autophagic vesicles and overwhelmed ALP function. Importantly, inhibition of mTORC1 signaling by rapamycin treatment aggravated the neurodegenerative phenotype in a TDP‐43‐depleted Drosophila model, whereas activation of mTORC1 signaling by PA treatment ameliorated the neurodegenerative phenotype. Taken together, our data indicate that impaired mTORC1 signaling and influenced ALP may contribute to TDP‐43‐mediated neurodegeneration. 相似文献
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Qian-qing Wang Xiang-cui Guo Li Li Zhi-hui Gao Mei Ji 《Journal of cellular physiology》2020,235(2):1339-1348
This study aimed to investigate the molecular mechanisms underlying the roles of metformin (MET) and Sorafenib (SOR) in the treatment of endometrial hyperplasia (EH) in polycystic ovary syndrome (PCOS). Effects of MET and SOR on the area of endometrium and myometrium were detected. Western blot analysis and immunohistochemistry assays were carried out to detect the levels of mammalian target of rapamycin complex 1 (mTORC1), mTORC2, LC3-II, P62, and Caspase-3 in rats and cultured cells. Furthermore, cell counting kit-8 assay and flow cytometry analysis was carried out to determine the apoptotic profiles of treated cells. MET and SOR could apparently decrease the areas of endometrium and myometrium in PCOS. MET notably enhanced the expression of LC3-II and Caspase-3 in PCOS while substantially reducing the level of mTORC1 and P62. Similarly, SOR also enhanced the expression of LC3-II and Caspase-3 in PCOS while substantially reducing the level of mTORC2 and P62. Treatment with MET and SOR significantly inhibited the proliferation of HCC-94 and HEC-1-A cells while promoting their apoptosis by upregulating the expression of Caspase-3. In cells treated with MET, the expression of mTORC1 and LC3-II was upregulated while the expression of P62 was downregulated. Similarly, in cells treated with SOR, the expression of mTORC2 and LC3-II was also upregulated while the expression of P62 was also downregulated. Furthermore, MET showed no effect on mTORC2 expression, while SOR showed no effect on mTORC1 expression. In this study, we suggested that MET and SOR alleviated the risk of EH in PCOS via the mTORC1/autophagy/apoptosis axis and mTORC2/autophagy/apoptosis axis, respectively. 相似文献
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Qian Gao Yuying Hou Zhe Li Jinyang Hu Dawei Huo Huimin Zheng Junjiang Zhang Xiaoyu Yao Rui Gao Xudong Wu Lei Sui 《Journal of cellular and molecular medicine》2021,25(14):6695-6708
Surface topography acts as an irreplaceable role in the long-term success of intraosseous implants. In this study, we prepared the hierarchical micro/nano topography using selective laser melting combined with alkali heat treatment (SLM-AHT) and explored the underlying mechanism of SLM-AHT surface-elicited osteogenesis. Our results show that cells cultured on SLM-AHT surface possess the largest number of mature FAs and exhibit a cytoskeleton reorganization compared with control groups. SLM-AHT surface could also significantly upregulate the expression of the cell adhesion-related molecule p-FAK, the osteogenic differentiation-related molecules RUNX2 and OCN as well as the mTORC2 signalling pathway key molecule Rictor. Notably, after the knocked-down of Rictor, there were no longer significant differences in the gene expression levels of the cell adhesion-related molecules and osteogenic differentiation-related molecules among the three titanium surfaces, and the cells on SLM-AHT surface failed to trigger cytoskeleton reorganization. In conclusion, the results suggest that mTORC2 can regulate the hierarchical micro/nano topography-mediated osteogenesis via cell adhesion and cytoskeletal reorganization. 相似文献
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Jiawen Wu Shengxiang Xiao Jianwen Ren Dingwei Zhang 《Journal of cellular biochemistry》2019,120(2):1773-1782
Metformin exhibits antiproliferative and proapoptotic effects in a variety of diseases, characterized by malignant and nonmalignant hyperplastic cells; however, the underlying molecular mechanism of metformin in psoriasis has not been elucidated. In the current study, we found that after metformin treatment the proliferation of human immortalized keratinocytes (HaCaT) was significantly inhibited, while cell apoptosis was increased in a dose-dependent manner, accompanied with enhanced protein expression of acyl-coenzyme A dehydrogenase 10 (ACAD10). Furthermore, mechanism analysis revealed that ACAD10 expression is induced by downregulated activities of mechanistic target of rapamycin 1 (mTORC1) signaling rather than AMP-activated protein kinase signaling. The inactivation of mTORC1 by rapamycin pretreatment or rotenone-induced mitochondrial complex inhibition showed a similar effect because of the metformin treatment on the proliferation and apoptosis of HaCaT keratinocytes. Overexpression of mTORC1 almost reversed the antiproliferation and proapoptosis effects induced by metformin. This study showed that the metformin treatment inhibited HaCaT cells proliferation and promoted apoptosis by affecting the mitochondrial-mTORC1 signaling and elevated the ACAD10 expression. Hence, metformin can be used as a potential therapeutic agent for psoriasis. 相似文献