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VHL-mediated disruption of Sox9 activity compromises β-cell identity and results in diabetes mellitus

Precise functioning of the pancreatic β cell is paramount to whole-body glucose homeostasis, and β-cell dysfunction contributes significantly to diabetes mellitus. Using transgenic mouse models, we demonstrate that deletion of the von Hippel-Lindau (Vhlh) gene (encoding an E3 ubiquitin ligase implic...

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Autores principales: Puri, Sapna, Akiyama, Haruhiko, Hebrok, Matthias
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3861670/
https://www.ncbi.nlm.nih.gov/pubmed/24298056
http://dx.doi.org/10.1101/gad.227785.113
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author Puri, Sapna
Akiyama, Haruhiko
Hebrok, Matthias
author_facet Puri, Sapna
Akiyama, Haruhiko
Hebrok, Matthias
author_sort Puri, Sapna
collection PubMed
description Precise functioning of the pancreatic β cell is paramount to whole-body glucose homeostasis, and β-cell dysfunction contributes significantly to diabetes mellitus. Using transgenic mouse models, we demonstrate that deletion of the von Hippel-Lindau (Vhlh) gene (encoding an E3 ubiquitin ligase implicated in, among other functions, oxygen sensing in pancreatic β cells) is deleterious to canonical β-cell gene expression. This triggers erroneous expression of factors normally active in progenitor cells, including effectors of the Notch, Wnt, and Hedgehog signaling cascades. Significantly, an up-regulation of the transcription factor Sox9, normally excluded from functional β cells, occurs upon deletion of Vhlh. Sox9 plays important roles during pancreas development but does not have a described role in the adult β cell. β-Cell-specific ectopic expression of Sox9 results in diabetes mellitus from similar perturbations in β-cell identity. These findings reveal that assaults on the β cell that impact the differentiation state of the cell have clear implications toward our understanding of diabetes mellitus.
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spelling pubmed-38616702014-06-01 VHL-mediated disruption of Sox9 activity compromises β-cell identity and results in diabetes mellitus Puri, Sapna Akiyama, Haruhiko Hebrok, Matthias Genes Dev Research Paper Precise functioning of the pancreatic β cell is paramount to whole-body glucose homeostasis, and β-cell dysfunction contributes significantly to diabetes mellitus. Using transgenic mouse models, we demonstrate that deletion of the von Hippel-Lindau (Vhlh) gene (encoding an E3 ubiquitin ligase implicated in, among other functions, oxygen sensing in pancreatic β cells) is deleterious to canonical β-cell gene expression. This triggers erroneous expression of factors normally active in progenitor cells, including effectors of the Notch, Wnt, and Hedgehog signaling cascades. Significantly, an up-regulation of the transcription factor Sox9, normally excluded from functional β cells, occurs upon deletion of Vhlh. Sox9 plays important roles during pancreas development but does not have a described role in the adult β cell. β-Cell-specific ectopic expression of Sox9 results in diabetes mellitus from similar perturbations in β-cell identity. These findings reveal that assaults on the β cell that impact the differentiation state of the cell have clear implications toward our understanding of diabetes mellitus. Cold Spring Harbor Laboratory Press 2013-12-01 /pmc/articles/PMC3861670/ /pubmed/24298056 http://dx.doi.org/10.1101/gad.227785.113 Text en © 2013 Puri et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/3.0/ This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 3.0 Unported), as described at http://creativecommons.org/licenses/by-nc/3.0/.
spellingShingle Research Paper
Puri, Sapna
Akiyama, Haruhiko
Hebrok, Matthias
VHL-mediated disruption of Sox9 activity compromises β-cell identity and results in diabetes mellitus
title VHL-mediated disruption of Sox9 activity compromises β-cell identity and results in diabetes mellitus
title_full VHL-mediated disruption of Sox9 activity compromises β-cell identity and results in diabetes mellitus
title_fullStr VHL-mediated disruption of Sox9 activity compromises β-cell identity and results in diabetes mellitus
title_full_unstemmed VHL-mediated disruption of Sox9 activity compromises β-cell identity and results in diabetes mellitus
title_short VHL-mediated disruption of Sox9 activity compromises β-cell identity and results in diabetes mellitus
title_sort vhl-mediated disruption of sox9 activity compromises β-cell identity and results in diabetes mellitus
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3861670/
https://www.ncbi.nlm.nih.gov/pubmed/24298056
http://dx.doi.org/10.1101/gad.227785.113
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