Jaroslaw Cendrowski1, Víctor J Sánchez-Arévalo Lobo1, Matthias Sendler2, Antonio Salas3, Jens-Peter Kühn4, Xavier Molero5, Rikiro Fukunaga6, Julia Mayerle2, Markus M Lerch2, Francisco X Real7. 1. Epithelial Carcinogenesis Group, Spanish National Cancer Research Center-CNIO, Madrid, Spain. 2. Department of Medicine A, University Medicine, Ernst-Moritz-Arndt University, Greifswald, Germany. 3. Servei d'Anatomia Patològica, Hospital Mútua Terrassa, Barcelona, Spain. 4. Institute of Radiology, University Medicine, Ernst-Moritz-University, Greifswald, Germany. 5. Exocrine Pancreas Research Unit, Hospital Universitari Vall d'Hebron, Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, CIBEREHD, Barcelona, Spain. 6. Osaka University of Pharmaceutical Sciences, Osaka, Japan. 7. Epithelial Carcinogenesis Group, Spanish National Cancer Research Center-CNIO, Madrid, Spain Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain.
Abstract
OBJECTIVE: Pancreatic acinar cell maturation is dependent on the activity of the pancreas transcription factor 1 (PTF1) complex. Induction of pancreatitis leads to MAP kinase activation and transient suppression of the acinar differentiation programme. We investigated the role of MAP kinase-interacting kinase 1 (Mnk1) in mouse exocrine pancreas development and in the response to secretagogue-induced pancreatitis. DESIGN: Mnk1 expression was analysed using immunohistochemistry, RT-qPCR and western blotting. Ptf1a binding to Mnk1 was assessed by chromatin immunoprecipitation and qPCR. Acute pancreatitis was induced in wild type and Mnk1(-/-) mice by 7 h intraperitoneal injections of caerulein. In vitro amylase secretion and trypsinogen activation were assessed using freshly isolated acinar cells. In vivo secretion was quantified by secretin-stimulated MRI. RESULTS: Mnk1 is expressed at the highest levels in pancreatic acinar cells and is a direct PTF1 target. Mnk1 is activated upon induction of pancreatitis and is indispensable for eIF4E phosphorylation. The pancreas of Mnk1(-/-) mice is histologically normal. Digestive enzyme content is significantly increased and c-Myc and Ccnd1 levels are reduced in Mnk1(-/-) mice. Upon induction of acute pancreatitis, Mnk1(-/-) mice show impaired eIF4E phosphorylation, activation of c-Myc and downregulation of zymogen content. Acinar cells show defective relocalisation of digestive enzymes, polarity defects and impaired secretory response in vitro and in vivo. CONCLUSIONS: Mnk1 is a novel pancreatic acinar cell-specific stress response kinase that regulates digestive enzyme abundance and eIF4E phosphorylation. It is required for the physiological secretory response of acinar cells and for the homeostatic response to caerulein administration during acute pancreatitis. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
OBJECTIVE:Pancreatic acinar cell maturation is dependent on the activity of the pancreas transcription factor 1 (PTF1) complex. Induction of pancreatitis leads to MAP kinase activation and transient suppression of the acinar differentiation programme. We investigated the role of MAP kinase-interacting kinase 1 (Mnk1) in mouse exocrine pancreas development and in the response to secretagogue-induced pancreatitis. DESIGN:Mnk1 expression was analysed using immunohistochemistry, RT-qPCR and western blotting. Ptf1a binding to Mnk1 was assessed by chromatin immunoprecipitation and qPCR. Acute pancreatitis was induced in wild type and Mnk1(-/-) mice by 7 h intraperitoneal injections of caerulein. In vitro amylase secretion and trypsinogen activation were assessed using freshly isolated acinar cells. In vivo secretion was quantified by secretin-stimulated MRI. RESULTS:Mnk1 is expressed at the highest levels in pancreatic acinar cells and is a direct PTF1 target. Mnk1 is activated upon induction of pancreatitis and is indispensable for eIF4E phosphorylation. The pancreas of Mnk1(-/-) mice is histologically normal. Digestive enzyme content is significantly increased and c-Myc and Ccnd1 levels are reduced in Mnk1(-/-) mice. Upon induction of acute pancreatitis, Mnk1(-/-) mice show impaired eIF4E phosphorylation, activation of c-Myc and downregulation of zymogen content. Acinar cells show defective relocalisation of digestive enzymes, polarity defects and impaired secretory response in vitro and in vivo. CONCLUSIONS:Mnk1 is a novel pancreatic acinar cell-specific stress response kinase that regulates digestive enzyme abundance and eIF4E phosphorylation. It is required for the physiological secretory response of acinar cells and for the homeostatic response to caerulein administration during acute pancreatitis. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
Authors: Chinh Q Hoang; Michael A Hale; Ana C Azevedo-Pouly; Hans P Elsässer; Tye G Deering; Spencer G Willet; Fong C Pan; Mark A Magnuson; Christopher V E Wright; Galvin H Swift; Raymond J MacDonald Journal: Mol Cell Biol Date: 2016-11-28 Impact factor: 4.272
Authors: Isidoro Cobo; Paola Martinelli; Marta Flández; Latifa Bakiri; Mingfeng Zhang; Enrique Carrillo-de-Santa-Pau; Jinping Jia; Víctor J Sánchez-Arévalo Lobo; Diego Megías; Irene Felipe; Natalia Del Pozo; Irene Millán; Liv Thommesen; Torunn Bruland; Sara H Olson; Jill Smith; Kristina Schoonjans; William R Bamlet; Gloria M Petersen; Núria Malats; Laufey T Amundadottir; Erwin F Wagner; Francisco X Real Journal: Nature Date: 2018-02-14 Impact factor: 49.962