VHL suppresses RAPTOR and inhibits mTORC1 signaling in clear cell renal cell carcinoma

Abstract Inactivation of the tumor suppressor von Hippel–Lindau (VHL) gene is a key event in hereditary and sporadic clear cell renal cell carcinomas (ccRCC). The mechanistic target of rapamycin (mTOR) signaling pathway is a fundamental regulator of cell growth and proliferation, and hyperactivation...

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Autores principales:	Athina Ganner, Christina Gehrke, Marinella Klein, Lena Thegtmeier, Tanja Matulenski, Laura Wingendorf, Lu Wang, Felicitas Pilz, Lars Greidl, Lisa Meid, Fruzsina Kotsis, Gerd Walz, Ian J. Frew, Elke Neumann-Haefelin
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/241005f7df754cd8bd98e91ced3ed44d
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spelling	oai:doaj.org-article:241005f7df754cd8bd98e91ced3ed44d2021-12-02T17:55:04ZVHL suppresses RAPTOR and inhibits mTORC1 signaling in clear cell renal cell carcinoma10.1038/s41598-021-94132-52045-2322https://doaj.org/article/241005f7df754cd8bd98e91ced3ed44d2021-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-94132-5https://doaj.org/toc/2045-2322Abstract Inactivation of the tumor suppressor von Hippel–Lindau (VHL) gene is a key event in hereditary and sporadic clear cell renal cell carcinomas (ccRCC). The mechanistic target of rapamycin (mTOR) signaling pathway is a fundamental regulator of cell growth and proliferation, and hyperactivation of mTOR signaling is a common finding in VHL-dependent ccRCC. Deregulation of mTOR signaling correlates with tumor progression and poor outcome in patients with ccRCC. Here, we report that the regulatory-associated protein of mTOR (RAPTOR) is strikingly repressed by VHL. VHL interacts with RAPTOR and increases RAPTOR degradation by ubiquitination, thereby inhibiting mTORC1 signaling. Consistent with hyperactivation of mTORC1 signaling in VHL-deficient ccRCC, we observed that loss of vhl-1 function in C. elegans increased mTORC1 activity, supporting an evolutionary conserved mechanism. Our work reveals important new mechanistic insight into deregulation of mTORC1 signaling in ccRCC and links VHL directly to the control of RAPTOR/mTORC1. This may represent a novel mechanism whereby loss of VHL affects organ integrity and tumor behavior.Athina GannerChristina GehrkeMarinella KleinLena ThegtmeierTanja MatulenskiLaura WingendorfLu WangFelicitas PilzLars GreidlLisa MeidFruzsina KotsisGerd WalzIan J. FrewElke Neumann-HaefelinNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Athina Ganner Christina Gehrke Marinella Klein Lena Thegtmeier Tanja Matulenski Laura Wingendorf Lu Wang Felicitas Pilz Lars Greidl Lisa Meid Fruzsina Kotsis Gerd Walz Ian J. Frew Elke Neumann-Haefelin VHL suppresses RAPTOR and inhibits mTORC1 signaling in clear cell renal cell carcinoma
description	Abstract Inactivation of the tumor suppressor von Hippel–Lindau (VHL) gene is a key event in hereditary and sporadic clear cell renal cell carcinomas (ccRCC). The mechanistic target of rapamycin (mTOR) signaling pathway is a fundamental regulator of cell growth and proliferation, and hyperactivation of mTOR signaling is a common finding in VHL-dependent ccRCC. Deregulation of mTOR signaling correlates with tumor progression and poor outcome in patients with ccRCC. Here, we report that the regulatory-associated protein of mTOR (RAPTOR) is strikingly repressed by VHL. VHL interacts with RAPTOR and increases RAPTOR degradation by ubiquitination, thereby inhibiting mTORC1 signaling. Consistent with hyperactivation of mTORC1 signaling in VHL-deficient ccRCC, we observed that loss of vhl-1 function in C. elegans increased mTORC1 activity, supporting an evolutionary conserved mechanism. Our work reveals important new mechanistic insight into deregulation of mTORC1 signaling in ccRCC and links VHL directly to the control of RAPTOR/mTORC1. This may represent a novel mechanism whereby loss of VHL affects organ integrity and tumor behavior.
format	article
author	Athina Ganner Christina Gehrke Marinella Klein Lena Thegtmeier Tanja Matulenski Laura Wingendorf Lu Wang Felicitas Pilz Lars Greidl Lisa Meid Fruzsina Kotsis Gerd Walz Ian J. Frew Elke Neumann-Haefelin
author_facet	Athina Ganner Christina Gehrke Marinella Klein Lena Thegtmeier Tanja Matulenski Laura Wingendorf Lu Wang Felicitas Pilz Lars Greidl Lisa Meid Fruzsina Kotsis Gerd Walz Ian J. Frew Elke Neumann-Haefelin
author_sort	Athina Ganner
title	VHL suppresses RAPTOR and inhibits mTORC1 signaling in clear cell renal cell carcinoma
title_short	VHL suppresses RAPTOR and inhibits mTORC1 signaling in clear cell renal cell carcinoma
title_full	VHL suppresses RAPTOR and inhibits mTORC1 signaling in clear cell renal cell carcinoma
title_fullStr	VHL suppresses RAPTOR and inhibits mTORC1 signaling in clear cell renal cell carcinoma
title_full_unstemmed	VHL suppresses RAPTOR and inhibits mTORC1 signaling in clear cell renal cell carcinoma
title_sort	vhl suppresses raptor and inhibits mtorc1 signaling in clear cell renal cell carcinoma
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/241005f7df754cd8bd98e91ced3ed44d
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VHL suppresses RAPTOR and inhibits mTORC1 signaling in clear cell renal cell carcinoma

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