Ptf1a inactivation in adult pancreatic acinar cells causes apoptosis through activation of the endoplasmic reticulum stress pathway

Abstract Pancreas transcription factor 1 subunit alpha (PTF1A) is one of the key regulators in pancreatogenesis. In adults, it transcribes digestive enzymes, but its other functions remain largely unknown. Recent conditional knockout studies using Ptf1a CreER/floxed heterozygous mouse models have fo...

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Autores principales:	Morito Sakikubo, Kenichiro Furuyama, Masashi Horiguchi, Shinichi Hosokawa, Yoshiki Aoyama, Kunihiko Tsuboi, Toshihiko Goto, Koji Hirata, Toshihiko Masui, Yuval Dor, Tomoyuki Fujiyama, Mikio Hoshino, Shinji Uemoto, Yoshiya Kawaguchi
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Adult Acinar Cells C/EBP Homologous Protein (CHOP) Inositol-requiring Enzyme 1 (IRE1) IRE1 Pathway ATF6 Pathway Medicine R Science Q
Acceso en línea:	https://doaj.org/article/d5cda09dbd034ebdab5ad4d1f0328baa
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spelling	oai:doaj.org-article:d5cda09dbd034ebdab5ad4d1f0328baa2021-12-02T15:08:16ZPtf1a inactivation in adult pancreatic acinar cells causes apoptosis through activation of the endoplasmic reticulum stress pathway10.1038/s41598-018-34093-42045-2322https://doaj.org/article/d5cda09dbd034ebdab5ad4d1f0328baa2018-10-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-34093-4https://doaj.org/toc/2045-2322Abstract Pancreas transcription factor 1 subunit alpha (PTF1A) is one of the key regulators in pancreatogenesis. In adults, it transcribes digestive enzymes, but its other functions remain largely unknown. Recent conditional knockout studies using Ptf1a CreER/floxed heterozygous mouse models have found PTF1A contributes to the identity maintenance of acinar cells and prevents tumorigenesis caused by the oncogenic gene Kras. However, Ptf1a heterozygote is known to behave differently from homozygote. To elucidate the effects of Ptf1a homozygous loss, we prepared Elastase-CreERTM; Ptf1a floxed/floxed mice and found that homozygous Ptf1a deletion in adult acinar cells causes severe apoptosis. Electron microscopy revealed endoplasmic reticulum (ER) stress, a known cause of unfolded protein responses (UPR). We confirmed that UPR was upregulated by the activating transcription factor 6 (ATF6) and protein kinase RNA (PKR)-like endoplasmic reticulum kinase (PERK) pathways, but not the inositol requiring enzyme 1 (IRE1) pathway. Furthermore, we detected the expression of CCAAT-enhancer-binding protein (C/EBP) homologous protein (CHOP), a pro-apoptotic factor, indicating the apoptosis was induced through UPR. Our homozygous model helps clarify the role PTF1A has on the homeostasis and pathogenesis of exocrine pancreas in mice.Morito SakikuboKenichiro FuruyamaMasashi HoriguchiShinichi HosokawaYoshiki AoyamaKunihiko TsuboiToshihiko GotoKoji HirataToshihiko MasuiYuval DorTomoyuki FujiyamaMikio HoshinoShinji UemotoYoshiya KawaguchiNature PortfolioarticleAdult Acinar CellsC/EBP Homologous Protein (CHOP)Inositol-requiring Enzyme 1 (IRE1)IRE1 PathwayATF6 PathwayMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-10 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Adult Acinar Cells C/EBP Homologous Protein (CHOP) Inositol-requiring Enzyme 1 (IRE1) IRE1 Pathway ATF6 Pathway Medicine R Science Q
spellingShingle	Adult Acinar Cells C/EBP Homologous Protein (CHOP) Inositol-requiring Enzyme 1 (IRE1) IRE1 Pathway ATF6 Pathway Medicine R Science Q Morito Sakikubo Kenichiro Furuyama Masashi Horiguchi Shinichi Hosokawa Yoshiki Aoyama Kunihiko Tsuboi Toshihiko Goto Koji Hirata Toshihiko Masui Yuval Dor Tomoyuki Fujiyama Mikio Hoshino Shinji Uemoto Yoshiya Kawaguchi Ptf1a inactivation in adult pancreatic acinar cells causes apoptosis through activation of the endoplasmic reticulum stress pathway
description	Abstract Pancreas transcription factor 1 subunit alpha (PTF1A) is one of the key regulators in pancreatogenesis. In adults, it transcribes digestive enzymes, but its other functions remain largely unknown. Recent conditional knockout studies using Ptf1a CreER/floxed heterozygous mouse models have found PTF1A contributes to the identity maintenance of acinar cells and prevents tumorigenesis caused by the oncogenic gene Kras. However, Ptf1a heterozygote is known to behave differently from homozygote. To elucidate the effects of Ptf1a homozygous loss, we prepared Elastase-CreERTM; Ptf1a floxed/floxed mice and found that homozygous Ptf1a deletion in adult acinar cells causes severe apoptosis. Electron microscopy revealed endoplasmic reticulum (ER) stress, a known cause of unfolded protein responses (UPR). We confirmed that UPR was upregulated by the activating transcription factor 6 (ATF6) and protein kinase RNA (PKR)-like endoplasmic reticulum kinase (PERK) pathways, but not the inositol requiring enzyme 1 (IRE1) pathway. Furthermore, we detected the expression of CCAAT-enhancer-binding protein (C/EBP) homologous protein (CHOP), a pro-apoptotic factor, indicating the apoptosis was induced through UPR. Our homozygous model helps clarify the role PTF1A has on the homeostasis and pathogenesis of exocrine pancreas in mice.
format	article
author	Morito Sakikubo Kenichiro Furuyama Masashi Horiguchi Shinichi Hosokawa Yoshiki Aoyama Kunihiko Tsuboi Toshihiko Goto Koji Hirata Toshihiko Masui Yuval Dor Tomoyuki Fujiyama Mikio Hoshino Shinji Uemoto Yoshiya Kawaguchi
author_facet	Morito Sakikubo Kenichiro Furuyama Masashi Horiguchi Shinichi Hosokawa Yoshiki Aoyama Kunihiko Tsuboi Toshihiko Goto Koji Hirata Toshihiko Masui Yuval Dor Tomoyuki Fujiyama Mikio Hoshino Shinji Uemoto Yoshiya Kawaguchi
author_sort	Morito Sakikubo
title	Ptf1a inactivation in adult pancreatic acinar cells causes apoptosis through activation of the endoplasmic reticulum stress pathway
title_short	Ptf1a inactivation in adult pancreatic acinar cells causes apoptosis through activation of the endoplasmic reticulum stress pathway
title_full	Ptf1a inactivation in adult pancreatic acinar cells causes apoptosis through activation of the endoplasmic reticulum stress pathway
title_fullStr	Ptf1a inactivation in adult pancreatic acinar cells causes apoptosis through activation of the endoplasmic reticulum stress pathway
title_full_unstemmed	Ptf1a inactivation in adult pancreatic acinar cells causes apoptosis through activation of the endoplasmic reticulum stress pathway
title_sort	ptf1a inactivation in adult pancreatic acinar cells causes apoptosis through activation of the endoplasmic reticulum stress pathway
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/d5cda09dbd034ebdab5ad4d1f0328baa
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Ptf1a inactivation in adult pancreatic acinar cells causes apoptosis through activation of the endoplasmic reticulum stress pathway

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