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PERK eIF2 alpha kinase is required to regulate the viability of the exocrine pancreas in mice

BACKGROUND: Deficiency of the PERK eIF2α kinase in humans and mice results in postnatal exocrine pancreatic atrophy as well as severe growth and metabolic anomalies in other organs and tissues. To determine if the exocrine pancreatic atrophy is due to a cell-autonomous defect, the Perk gene was spec...

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Autores principales: Iida, Kaori, Li, Yulin, McGrath, Barbara C, Frank, Ami, Cavener, Douglas R
Formato: Texto
Lenguaje:English
Publicado: BioMed Central 2007
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2072952/
https://www.ncbi.nlm.nih.gov/pubmed/17727724
http://dx.doi.org/10.1186/1471-2121-8-38
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author Iida, Kaori
Li, Yulin
McGrath, Barbara C
Frank, Ami
Cavener, Douglas R
author_facet Iida, Kaori
Li, Yulin
McGrath, Barbara C
Frank, Ami
Cavener, Douglas R
author_sort Iida, Kaori
collection PubMed
description BACKGROUND: Deficiency of the PERK eIF2α kinase in humans and mice results in postnatal exocrine pancreatic atrophy as well as severe growth and metabolic anomalies in other organs and tissues. To determine if the exocrine pancreatic atrophy is due to a cell-autonomous defect, the Perk gene was specifically ablated in acinar cells of the exocrine pancreas in mice. RESULTS: We show that expression of PERK in the acinar cells is required to maintain their viability but is not required for normal protein synthesis and secretion. Exocrine pancreatic atrophy in PERK-deficient mice was previously attributed to uncontrolled ER-stress followed by apoptotic cell death based on studies in cultured fibroblasts. However, we have found no evidence for perturbations in the endoplasmic reticulum or ER-stress and show that acinar cells succumb to a non-apoptotic form of cell death, oncosis, which is associated with a pronounced inflammatory response and induction of the pancreatitis stress response genes. We also show that mice carrying a knockout mutation of PERK's downstream target, ATF4, exhibit pancreatic deficiency caused by developmental defects and that mice ablated for ATF4's transcriptional target CHOP have a normal exocrine pancreas. CONCLUSION: We conclude that PERK modulates secretory capacity of the exocrine pancreas by regulating cell viability of acinar cells.
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spelling pubmed-20729522007-11-10 PERK eIF2 alpha kinase is required to regulate the viability of the exocrine pancreas in mice Iida, Kaori Li, Yulin McGrath, Barbara C Frank, Ami Cavener, Douglas R BMC Cell Biol Research Article BACKGROUND: Deficiency of the PERK eIF2α kinase in humans and mice results in postnatal exocrine pancreatic atrophy as well as severe growth and metabolic anomalies in other organs and tissues. To determine if the exocrine pancreatic atrophy is due to a cell-autonomous defect, the Perk gene was specifically ablated in acinar cells of the exocrine pancreas in mice. RESULTS: We show that expression of PERK in the acinar cells is required to maintain their viability but is not required for normal protein synthesis and secretion. Exocrine pancreatic atrophy in PERK-deficient mice was previously attributed to uncontrolled ER-stress followed by apoptotic cell death based on studies in cultured fibroblasts. However, we have found no evidence for perturbations in the endoplasmic reticulum or ER-stress and show that acinar cells succumb to a non-apoptotic form of cell death, oncosis, which is associated with a pronounced inflammatory response and induction of the pancreatitis stress response genes. We also show that mice carrying a knockout mutation of PERK's downstream target, ATF4, exhibit pancreatic deficiency caused by developmental defects and that mice ablated for ATF4's transcriptional target CHOP have a normal exocrine pancreas. CONCLUSION: We conclude that PERK modulates secretory capacity of the exocrine pancreas by regulating cell viability of acinar cells. BioMed Central 2007-08-29 /pmc/articles/PMC2072952/ /pubmed/17727724 http://dx.doi.org/10.1186/1471-2121-8-38 Text en Copyright © 2007 Iida et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( (http://creativecommons.org/licenses/by/2.0) ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Iida, Kaori
Li, Yulin
McGrath, Barbara C
Frank, Ami
Cavener, Douglas R
PERK eIF2 alpha kinase is required to regulate the viability of the exocrine pancreas in mice
title PERK eIF2 alpha kinase is required to regulate the viability of the exocrine pancreas in mice
title_full PERK eIF2 alpha kinase is required to regulate the viability of the exocrine pancreas in mice
title_fullStr PERK eIF2 alpha kinase is required to regulate the viability of the exocrine pancreas in mice
title_full_unstemmed PERK eIF2 alpha kinase is required to regulate the viability of the exocrine pancreas in mice
title_short PERK eIF2 alpha kinase is required to regulate the viability of the exocrine pancreas in mice
title_sort perk eif2 alpha kinase is required to regulate the viability of the exocrine pancreas in mice
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2072952/
https://www.ncbi.nlm.nih.gov/pubmed/17727724
http://dx.doi.org/10.1186/1471-2121-8-38
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