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Expression of Human Mutant Preproinsulins Induced Unfolded Protein Response, Gadd45 Expression, JAK-STAT Activation, and Growth Inhibition in Drosophila

Mutations in the insulin gene (INS) are frequently associated with human permanent neonatal diabetes mellitus. However, the mechanisms underlying the onset of this genetic disease is not sufficiently decoded. We induced expression of two types of human mutant INSs in Drosophila using its ectopic exp...

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Autores principales: Yamazoe, Tatsuki, Nakahara, Yasuyuki, Katsube, Hiroka, Inoue, Yoshihiro H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8584581/
https://www.ncbi.nlm.nih.gov/pubmed/34769468
http://dx.doi.org/10.3390/ijms222112038
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author Yamazoe, Tatsuki
Nakahara, Yasuyuki
Katsube, Hiroka
Inoue, Yoshihiro H.
author_facet Yamazoe, Tatsuki
Nakahara, Yasuyuki
Katsube, Hiroka
Inoue, Yoshihiro H.
author_sort Yamazoe, Tatsuki
collection PubMed
description Mutations in the insulin gene (INS) are frequently associated with human permanent neonatal diabetes mellitus. However, the mechanisms underlying the onset of this genetic disease is not sufficiently decoded. We induced expression of two types of human mutant INSs in Drosophila using its ectopic expression system and investigated the resultant responses in development. Expression of the wild-type preproinsulin in the insulin-producing cells (IPCs) throughout the larval stage led to a stimulation of the overall and wing growth. However, ectopic expression of human mutant preproinsulins, hINS(C96Y) and hINS(LB15YB16delinsH), neither of which secreted from the β-cells, could not stimulate the Drosophila growth. Furthermore, neither of the mutant polypeptides induced caspase activation leading to apoptosis. Instead, they induced expression of several markers indicating the activation of unfolded protein response, such as ER stress-dependent Xbp1 mRNA splicing and ER chaperone induction. We newly found that the mutant polypeptides induced the expression of Growth arrest and DNA-damage-inducible 45 (Gadd45) in imaginal disc cells. ER stress induced by hINS(C96Y) also activated the JAK-STAT signaling, involved in inflammatory responses. Collectively, we speculate that the diabetes-like growth defects appeared as a consequence of the human mutant preproinsulin expression was involved in dysfunction of the IPCs, rather than apoptosis.
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spelling pubmed-85845812021-11-12 Expression of Human Mutant Preproinsulins Induced Unfolded Protein Response, Gadd45 Expression, JAK-STAT Activation, and Growth Inhibition in Drosophila Yamazoe, Tatsuki Nakahara, Yasuyuki Katsube, Hiroka Inoue, Yoshihiro H. Int J Mol Sci Article Mutations in the insulin gene (INS) are frequently associated with human permanent neonatal diabetes mellitus. However, the mechanisms underlying the onset of this genetic disease is not sufficiently decoded. We induced expression of two types of human mutant INSs in Drosophila using its ectopic expression system and investigated the resultant responses in development. Expression of the wild-type preproinsulin in the insulin-producing cells (IPCs) throughout the larval stage led to a stimulation of the overall and wing growth. However, ectopic expression of human mutant preproinsulins, hINS(C96Y) and hINS(LB15YB16delinsH), neither of which secreted from the β-cells, could not stimulate the Drosophila growth. Furthermore, neither of the mutant polypeptides induced caspase activation leading to apoptosis. Instead, they induced expression of several markers indicating the activation of unfolded protein response, such as ER stress-dependent Xbp1 mRNA splicing and ER chaperone induction. We newly found that the mutant polypeptides induced the expression of Growth arrest and DNA-damage-inducible 45 (Gadd45) in imaginal disc cells. ER stress induced by hINS(C96Y) also activated the JAK-STAT signaling, involved in inflammatory responses. Collectively, we speculate that the diabetes-like growth defects appeared as a consequence of the human mutant preproinsulin expression was involved in dysfunction of the IPCs, rather than apoptosis. MDPI 2021-11-07 /pmc/articles/PMC8584581/ /pubmed/34769468 http://dx.doi.org/10.3390/ijms222112038 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Yamazoe, Tatsuki
Nakahara, Yasuyuki
Katsube, Hiroka
Inoue, Yoshihiro H.
Expression of Human Mutant Preproinsulins Induced Unfolded Protein Response, Gadd45 Expression, JAK-STAT Activation, and Growth Inhibition in Drosophila
title Expression of Human Mutant Preproinsulins Induced Unfolded Protein Response, Gadd45 Expression, JAK-STAT Activation, and Growth Inhibition in Drosophila
title_full Expression of Human Mutant Preproinsulins Induced Unfolded Protein Response, Gadd45 Expression, JAK-STAT Activation, and Growth Inhibition in Drosophila
title_fullStr Expression of Human Mutant Preproinsulins Induced Unfolded Protein Response, Gadd45 Expression, JAK-STAT Activation, and Growth Inhibition in Drosophila
title_full_unstemmed Expression of Human Mutant Preproinsulins Induced Unfolded Protein Response, Gadd45 Expression, JAK-STAT Activation, and Growth Inhibition in Drosophila
title_short Expression of Human Mutant Preproinsulins Induced Unfolded Protein Response, Gadd45 Expression, JAK-STAT Activation, and Growth Inhibition in Drosophila
title_sort expression of human mutant preproinsulins induced unfolded protein response, gadd45 expression, jak-stat activation, and growth inhibition in drosophila
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8584581/
https://www.ncbi.nlm.nih.gov/pubmed/34769468
http://dx.doi.org/10.3390/ijms222112038
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