mTOR: from growth signal integration to cancer, diabetes and ageing

Zoncu, Roberto; Efeyan, Alejo; Sabatini, David M.

doi:10.1038/nrm3025

Cited by 3,576 publications

(4,078 citation statements)

References 205 publications

(220 reference statements)

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“…One possible explanation for the more extensive requirement for kinases and phosphatases to prevent autophagy is that autophagy might be a default state that is subject to negative regulation in the presence of multiple signals that indicate favourable growth conditions. Such a notion is consistent with the previous suggestion that mTor is an integrator of multiple favourable growth conditions to modulate both protein synthesis and degradation 48, 49. This also raises the question of the relative importance of autophagic‐mediated as opposed to proteasome‐mediated protein degradation for maintaining human muscle homeostasis.…”

Section: Discussionsupporting

confidence: 90%

Functional phosphatome requirement for protein homeostasis, networked mitochondria, and sarcomere structure in C. elegans muscle

Lehmann

Bass

Barratt

et al. 2017

J cachexia sarcopenia muscle

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BackgroundSkeletal muscle is central to locomotion and metabolic homeostasis. The laboratory worm Caenorhabditis elegans has been developed into a genomic model for assessing the genes and signals that regulate muscle development and protein degradation. Past work has identified a receptor tyrosine kinase signalling network that combinatorially controls autophagy, nerve signal to muscle to oppose proteasome‐based degradation, and extracellular matrix‐based signals that control calpain and caspase activation. The last two discoveries were enabled by following up results from a functional genomic screen of known regulators of muscle. Recently, a screen of the kinome requirement for muscle homeostasis identified roughly 40% of kinases as required for C. elegans muscle health; 80 have identified human orthologues and 53 are known to be expressed in skeletal muscle. To complement this kinome screen, here, we screen most of the phosphatases in C. elegans . MethodsRNA interference was used to knockdown phosphatase‐encoding genes. Knockdown was first conducted during development with positive results also knocked down only in fully developed adult muscle. Protein homeostasis, mitochondrial structure, and sarcomere structure were assessed using transgenic reporter proteins. Genes identified as being required to prevent protein degradation were also knocked down in conditions that blocked proteasome or autophagic degradation. Genes identified as being required to prevent autophagic degradation were also assessed for autophagic vesicle accumulation using another transgenic reporter. Lastly, bioinformatics were used to look for overlap between kinases and phosphatases required for muscle homeostasis, and the prediction that one phosphatase was required to prevent mitogen‐activated protein kinase activation was assessed by western blot.ResultsA little over half of all phosphatases are each required to prevent abnormal development or maintenance of muscle. Eighty‐six of these phosphatases have known human orthologues, 57 of which are known to be expressed in human skeletal muscle. Of the phosphatases required to prevent abnormal muscle protein degradation, roughly half are required to prevent increased autophagy.ConclusionsA significant portion of both the kinome and phosphatome are required for establishing and maintaining C. elegans muscle health. Autophagy appears to be the most commonly triggered form of protein degradation in response to disruption of phosphorylation‐based signalling. The results from these screens provide measurable phenotypes for analysing the combined contribution of kinases and phosphatases in a multi‐cellular organism and suggest new potential regulators of human skeletal muscle for further analysis.

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Section: Discussionsupporting

confidence: 90%

Functional phosphatome requirement for protein homeostasis, networked mitochondria, and sarcomere structure in C. elegans muscle

Lehmann

Bass

Barratt

et al. 2017

J cachexia sarcopenia muscle

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“…Similar to that, immunofluorescence staining showed no significant difference in p‐S6 and p‐AKT473 expression between Clpp −/− and Clpp +/+ GV oocytes at 3 months (Figure 6e–g), while both p‐S6 and p‐AKT473 expressions were higher in Clpp −/− GV oocytes at 6 months ( p < 0.001; Figure 6h–j), indicating that Clpp deletion results in the activation of mTOR pathway. We then tested three additional proteins that mediate mTOR activity, p‐4EBP1 and p‐S6K for mTORC1 (Zoncu, Efeyan & Sabatini, 2011), and p‐mTOR2481 for mTORC2 (Copp, Manning & Hunter, 2009). The expression of these three more proteins was also significantly increased in 6‐month‐old Clpp −/− mice ovaries (Figure 6c–d).…”

Section: Resultsmentioning

confidence: 99%

Mitochondrial unfolded protein response gene Clpp is required to maintain ovarian follicular reserve during aging, for oocyte competence, and development of pre‐implantation embryos

et al. 2018

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SummaryCaseinolytic peptidase P mediates degradation of unfolded mitochondrial proteins and activates mitochondrial unfolded protein response (mtUPR) to maintain protein homeostasis. Clpp −/− female mice generate a lower number of mature oocytes and two‐cell embryos, and no blastocysts. Clpp −/− oocytes have smaller mitochondria, with lower aspect ratio (length/width), and decreased expression of genes that promote fusion. A 4‐fold increase in atretic follicles at 3 months, and reduced number of primordial follicles at 6–12 months are observed in Clpp −/− ovaries. This is associated with upregulation of p‐S6, p‐S6K, p‐4EBP1 and p‐AKT473, p‐mTOR2481 consistent with mTORC1 and mTORC2 activation, respectively, and Clpp −/− oocyte competence is partially rescued by mTOR inhibitor rapamycin. Our findings demonstrate that CLPP is required for oocyte and embryo development and oocyte mitochondrial function and dynamics. Absence of CLPP results in mTOR pathway activation, and accelerated depletion of ovarian follicular reserve.

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“…Activation of mTORC1 in cancer has been shown in numerous studies (Zoncu et al , 2011). mTORC1 and MYC have overlapping functions, including stimulating effects on cell growth and proliferation, ribosome biogenesis, and protein synthesis.…”

Section: Discussionmentioning

confidence: 98%

Tuberous sclerosis complex is required for tumor maintenance in MYC‐driven Burkitt's lymphoma

et al. 2018

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The tuberous sclerosis complex (TSC) 1/2 is a negative regulator of the nutrient‐sensing kinase mechanistic target of rapamycin complex (mTORC1), and its function is generally associated with tumor suppression. Nevertheless, biallelic loss of function of TSC1 or TSC2 is rarely found in malignant tumors. Here, we show that TSC1/2 is highly expressed in Burkitt's lymphoma cell lines and patient samples of human Burkitt's lymphoma, a prototypical MYC‐driven cancer. Mechanistically, we show that MYC induces TSC1 expression by transcriptional activation of the TSC1 promoter and repression of miR‐15a. TSC1 knockdown results in elevated mTORC1‐dependent mitochondrial respiration enhanced ROS production and apoptosis. Moreover, TSC1 deficiency attenuates tumor growth in a xenograft mouse model. Our study reveals a novel role for TSC1 in securing homeostasis between MYC and mTORC1 that is required for cell survival and tumor maintenance in Burkitt's lymphoma. The study identifies TSC1/2 inhibition and/or mTORC1 hyperactivation as a novel therapeutic strategy for MYC‐driven cancers.

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mTOR: from growth signal integration to cancer, diabetes and ageing

Cited by 3,576 publications

References 205 publications

Functional phosphatome requirement for protein homeostasis, networked mitochondria, and sarcomere structure in C. elegans muscle

Functional phosphatome requirement for protein homeostasis, networked mitochondria, and sarcomere structure in C. elegans muscle

Mitochondrial unfolded protein response gene Clpp is required to maintain ovarian follicular reserve during aging, for oocyte competence, and development of pre‐implantation embryos

Tuberous sclerosis complex is required for tumor maintenance in MYC‐driven Burkitt's lymphoma

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