NFIC regulates ribosomal biology and ER stress in pancreatic acinar cells and restrains PDAC initiation

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• dc.contributor.author Cobo, Isidoro
• dc.contributor.author Paliwal, Sumit
• dc.contributor.author Bodas, Cristina
• dc.contributor.author Felipe, Irene
• dc.contributor.author Melià-Alomà, Júlia
• dc.contributor.author Torres, Ariadna
• dc.contributor.author Martínez-Villarreal, Jaime
• dc.contributor.author Malumbres, Marina
• dc.contributor.author García, Fernando
• dc.contributor.author Millán, Irene
• dc.contributor.author Pozo, Natalia del
• dc.contributor.author Park, Joo-Cheol
• dc.contributor.author MacDonald, Ray J.
• dc.contributor.author Muñoz, Javier
• dc.contributor.author Méndez, Raúl
• dc.contributor.author Real, Francisco X.
• dc.date.accessioned 2023-10-06T06:03:30Z
• dc.date.available 2023-10-06T06:03:30Z
• dc.date.issued 2023
• dc.description.abstract Pancreatic acinar cells rely on PTF1 and other transcription factors to deploy their transcriptional program. We identify NFIC as a NR5A2 interactor and regulator of acinar differentiation. NFIC binding sites are enriched in NR5A2 ChIP-Sequencing peaks. Nfic knockout mice have a smaller, histologically normal, pancreas with reduced acinar gene expression. NFIC binds and regulates the promoters of acinar genes and those involved in RNA/protein metabolism, and Nfic knockout pancreata show defective ribosomal RNA maturation. NFIC dampens the endoplasmic reticulum stress program through binding to gene promoters and is required for resolution of Tunicamycin-mediated stress. NFIC is down-regulated during caerulein pancreatitis and is required for recovery after damage. Normal human pancreata with low levels of NFIC transcripts display reduced expression of genes down-regulated in Nfic knockout mice. NFIC expression is down-regulated in mouse and human pancreatic ductal adenocarcinoma. Consistently, Nfic knockout mice develop a higher number of mutant Kras-driven pre-neoplastic lesions.
• dc.description.sponsorship This work was supported, in part, by grants SAF2011-29530, SAF2015-70553-R, RTI2018-101071-B-I00 from Ministerio de Ciencia, Innovación y Universidades (Madrid, Spain) (co-funded by the ERDF-EU) and RTICC from Instituto de Salud Carlos III (RD12/0036/0034) to FXR and grants PID2020-119533GB-I00, from Ministerio de Ciencia, Innovación y Universidades (Madrid, Spain), and GCB15152955MÉND, from the Spanish Association Against Cancer (AECC), to RM. I.C. was recipient of a Beca de Formación del Personal Investigador from Ministerio de Economía y Competitividad (Madrid, Spain). The research leading to these results has received funding from People Programme (Marie Curie Actions) of the European Union’s Seventh Framework Programme (FP7/2007-2013) (REA grant agreement n° 608765”). S.P. was supported by a Juan de la Cierva Programme fellowship from Ministerio de Ciencia, Innovación y Universidades. C.B. is supported by a FPI Fellowship from Ministerio de Ciencia, Innovación y Universidades. I.M. was supported by a Fellowship from Fundació Bancària La Caixa (ID 100010434) (grant number LCF/BQ/ES18/11670009). CNIO is supported by Ministerio de Ciencia, Innovación y Universidades as a Centro de Excelencia Severo Ochoa SEV-2015-0510.
• dc.format.mimetype application/pdf
• dc.identifier.citation Cobo I, Paliwal S, Bodas C, Felipe I, Melià-Alomà J, Torres A, Martínez-Villarreal J, Malumbres M, García F, Millán I, Del Pozo N, Park JC, MacDonald RJ, Muñoz J, Méndez R, Real FX. NFIC regulates ribosomal biology and ER stress in pancreatic acinar cells and restrains PDAC initiation. Nat Commun. 2023 Jun 23;14(1):3761. DOI: 10.1038/s41467-023-39291-x
• dc.identifier.doi http://dx.doi.org/10.1038/s41467-023-39291-x
• dc.identifier.issn 2041-1723
• dc.identifier.uri http://hdl.handle.net/10230/58051
• dc.language.iso eng
• dc.publisher Nature Research
• dc.relation.ispartof Nat Commun. 2023 Jun 23;14(1):3761
• dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/608765
• dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/SAF2011-29530
• dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2015-70553-R
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/RTI2018-101071-B-I00
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2020-119533GB-I00
• dc.rights © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword Cancer
• dc.subject.keyword Pancreatic disease
• dc.title NFIC regulates ribosomal biology and ER stress in pancreatic acinar cells and restrains PDAC initiation
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion