Reduction of Derlin activity suppresses Notch-dependent tumours in the C. elegans germ line.

Regulating the balance between self-renewal (proliferation) and differentiation is key to the long-term functioning of all stem cell pools. In the Caenorhabditis elegans germline, the primary signal controlling this balance is the conserved Notch signaling pathway. Gain-of-function mutations in the...

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Autores principales:	Ramya Singh, Ryan B Smit, Xin Wang, Chris Wang, Hilary Racher, Dave Hansen
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Genetics QH426-470
Acceso en línea:	https://doaj.org/article/aa2dd44ee7fb48f49da522b91b00bc1a
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spelling	oai:doaj.org-article:aa2dd44ee7fb48f49da522b91b00bc1a2021-12-02T20:03:02ZReduction of Derlin activity suppresses Notch-dependent tumours in the C. elegans germ line.1553-73901553-740410.1371/journal.pgen.1009687https://doaj.org/article/aa2dd44ee7fb48f49da522b91b00bc1a2021-09-01T00:00:00Zhttps://doi.org/10.1371/journal.pgen.1009687https://doaj.org/toc/1553-7390https://doaj.org/toc/1553-7404Regulating the balance between self-renewal (proliferation) and differentiation is key to the long-term functioning of all stem cell pools. In the Caenorhabditis elegans germline, the primary signal controlling this balance is the conserved Notch signaling pathway. Gain-of-function mutations in the GLP-1/Notch receptor cause increased stem cell self-renewal, resulting in a tumour of proliferating germline stem cells. Notch gain-of-function mutations activate the receptor, even in the presence of little or no ligand, and have been associated with many human diseases, including cancers. We demonstrate that reduction in CUP-2 and DER-2 function, which are Derlin family proteins that function in endoplasmic reticulum-associated degradation (ERAD), suppresses the C. elegans germline over-proliferation phenotype associated with glp-1(gain-of-function) mutations. We further demonstrate that their reduction does not suppress other mutations that cause over-proliferation, suggesting that over-proliferation suppression due to loss of Derlin activity is specific to glp-1/Notch (gain-of-function) mutations. Reduction of CUP-2 Derlin activity reduces the expression of a read-out of GLP-1/Notch signaling, suggesting that the suppression of over-proliferation in Derlin loss-of-function mutants is due to a reduction in the activity of the mutated GLP-1/Notch(GF) receptor. Over-proliferation suppression in cup-2 mutants is only seen when the Unfolded Protein Response (UPR) is functioning properly, suggesting that the suppression, and reduction in GLP-1/Notch signaling levels, observed in Derlin mutants may be the result of activation of the UPR. Chemically inducing ER stress also suppress glp-1(gf) over-proliferation but not other mutations that cause over-proliferation. Therefore, ER stress and activation of the UPR may help correct for increased GLP-1/Notch signaling levels, and associated over-proliferation, in the C. elegans germline.Ramya SinghRyan B SmitXin WangChris WangHilary RacherDave HansenPublic Library of Science (PLoS)articleGeneticsQH426-470ENPLoS Genetics, Vol 17, Iss 9, p e1009687 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Genetics QH426-470
spellingShingle	Genetics QH426-470 Ramya Singh Ryan B Smit Xin Wang Chris Wang Hilary Racher Dave Hansen Reduction of Derlin activity suppresses Notch-dependent tumours in the C. elegans germ line.
description	Regulating the balance between self-renewal (proliferation) and differentiation is key to the long-term functioning of all stem cell pools. In the Caenorhabditis elegans germline, the primary signal controlling this balance is the conserved Notch signaling pathway. Gain-of-function mutations in the GLP-1/Notch receptor cause increased stem cell self-renewal, resulting in a tumour of proliferating germline stem cells. Notch gain-of-function mutations activate the receptor, even in the presence of little or no ligand, and have been associated with many human diseases, including cancers. We demonstrate that reduction in CUP-2 and DER-2 function, which are Derlin family proteins that function in endoplasmic reticulum-associated degradation (ERAD), suppresses the C. elegans germline over-proliferation phenotype associated with glp-1(gain-of-function) mutations. We further demonstrate that their reduction does not suppress other mutations that cause over-proliferation, suggesting that over-proliferation suppression due to loss of Derlin activity is specific to glp-1/Notch (gain-of-function) mutations. Reduction of CUP-2 Derlin activity reduces the expression of a read-out of GLP-1/Notch signaling, suggesting that the suppression of over-proliferation in Derlin loss-of-function mutants is due to a reduction in the activity of the mutated GLP-1/Notch(GF) receptor. Over-proliferation suppression in cup-2 mutants is only seen when the Unfolded Protein Response (UPR) is functioning properly, suggesting that the suppression, and reduction in GLP-1/Notch signaling levels, observed in Derlin mutants may be the result of activation of the UPR. Chemically inducing ER stress also suppress glp-1(gf) over-proliferation but not other mutations that cause over-proliferation. Therefore, ER stress and activation of the UPR may help correct for increased GLP-1/Notch signaling levels, and associated over-proliferation, in the C. elegans germline.
format	article
author	Ramya Singh Ryan B Smit Xin Wang Chris Wang Hilary Racher Dave Hansen
author_facet	Ramya Singh Ryan B Smit Xin Wang Chris Wang Hilary Racher Dave Hansen
author_sort	Ramya Singh
title	Reduction of Derlin activity suppresses Notch-dependent tumours in the C. elegans germ line.
title_short	Reduction of Derlin activity suppresses Notch-dependent tumours in the C. elegans germ line.
title_full	Reduction of Derlin activity suppresses Notch-dependent tumours in the C. elegans germ line.
title_fullStr	Reduction of Derlin activity suppresses Notch-dependent tumours in the C. elegans germ line.
title_full_unstemmed	Reduction of Derlin activity suppresses Notch-dependent tumours in the C. elegans germ line.
title_sort	reduction of derlin activity suppresses notch-dependent tumours in the c. elegans germ line.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/aa2dd44ee7fb48f49da522b91b00bc1a
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Reduction of Derlin activity suppresses Notch-dependent tumours in the C. elegans germ line.

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