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Regulation of YAP by mTOR and autophagy reveals a therapeutic target of tuberous sclerosis complex

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 pathw...

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Autores principales: Liang, Ning, Zhang, Chi, Dill, Patricia, Panasyuk, Ganna, Pion, Delphine, Koka, Vonda, Gallazzini, Morgan, Olson, Eric N., Lam, Hilaire, Henske, Elizabeth P., Dong, Zheng, Apte, Udayan, Pallet, Nicolas, Johnson, Randy L., Terzi, Fabiola, Kwiatkowski, David J., Scoazec, Jean-Yves, Martignoni, Guido, Pende, Mario
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4203941/
https://www.ncbi.nlm.nih.gov/pubmed/25288394
http://dx.doi.org/10.1084/jem.20140341
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author Liang, Ning
Zhang, Chi
Dill, Patricia
Panasyuk, Ganna
Pion, Delphine
Koka, Vonda
Gallazzini, Morgan
Olson, Eric N.
Lam, Hilaire
Henske, Elizabeth P.
Dong, Zheng
Apte, Udayan
Pallet, Nicolas
Johnson, Randy L.
Terzi, Fabiola
Kwiatkowski, David J.
Scoazec, Jean-Yves
Martignoni, Guido
Pende, Mario
author_facet Liang, Ning
Zhang, Chi
Dill, Patricia
Panasyuk, Ganna
Pion, Delphine
Koka, Vonda
Gallazzini, Morgan
Olson, Eric N.
Lam, Hilaire
Henske, Elizabeth P.
Dong, Zheng
Apte, Udayan
Pallet, Nicolas
Johnson, Randy L.
Terzi, Fabiola
Kwiatkowski, David J.
Scoazec, Jean-Yves
Martignoni, Guido
Pende, Mario
author_sort Liang, Ning
collection PubMed
description 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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spelling pubmed-42039412015-04-20 Regulation of YAP by mTOR and autophagy reveals a therapeutic target of tuberous sclerosis complex Liang, Ning Zhang, Chi Dill, Patricia Panasyuk, Ganna Pion, Delphine Koka, Vonda Gallazzini, Morgan Olson, Eric N. Lam, Hilaire Henske, Elizabeth P. Dong, Zheng Apte, Udayan Pallet, Nicolas Johnson, Randy L. Terzi, Fabiola Kwiatkowski, David J. Scoazec, Jean-Yves Martignoni, Guido Pende, Mario J Exp Med Article 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. The Rockefeller University Press 2014-10-20 /pmc/articles/PMC4203941/ /pubmed/25288394 http://dx.doi.org/10.1084/jem.20140341 Text en © 2014 Liang et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Article
Liang, Ning
Zhang, Chi
Dill, Patricia
Panasyuk, Ganna
Pion, Delphine
Koka, Vonda
Gallazzini, Morgan
Olson, Eric N.
Lam, Hilaire
Henske, Elizabeth P.
Dong, Zheng
Apte, Udayan
Pallet, Nicolas
Johnson, Randy L.
Terzi, Fabiola
Kwiatkowski, David J.
Scoazec, Jean-Yves
Martignoni, Guido
Pende, Mario
Regulation of YAP by mTOR and autophagy reveals a therapeutic target of tuberous sclerosis complex
title Regulation of YAP by mTOR and autophagy reveals a therapeutic target of tuberous sclerosis complex
title_full Regulation of YAP by mTOR and autophagy reveals a therapeutic target of tuberous sclerosis complex
title_fullStr Regulation of YAP by mTOR and autophagy reveals a therapeutic target of tuberous sclerosis complex
title_full_unstemmed Regulation of YAP by mTOR and autophagy reveals a therapeutic target of tuberous sclerosis complex
title_short Regulation of YAP by mTOR and autophagy reveals a therapeutic target of tuberous sclerosis complex
title_sort regulation of yap by mtor and autophagy reveals a therapeutic target of tuberous sclerosis complex
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4203941/
https://www.ncbi.nlm.nih.gov/pubmed/25288394
http://dx.doi.org/10.1084/jem.20140341
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