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Mnk1 is a novel acinar cell-specific kinase required for exocrine pancreatic secretion and response to pancreatitis in mice
  1. Jaroslaw Cendrowski1,
  2. Víctor J Sánchez-Arévalo Lobo1,
  3. Matthias Sendler2,
  4. Antonio Salas3,
  5. Jens-Peter Kühn4,
  6. Xavier Molero5,
  7. Rikiro Fukunaga6,
  8. Julia Mayerle2,
  9. Markus M Lerch2,
  10. Francisco X Real1,7
  1. 1Epithelial Carcinogenesis Group, Spanish National Cancer Research Center-CNIO, Madrid, Spain
  2. 2Department of Medicine A, University Medicine, Ernst-Moritz-Arndt University, Greifswald, Germany
  3. 3Servei d'Anatomia Patològica, Hospital Mútua Terrassa, Barcelona, Spain
  4. 4Institute of Radiology, University Medicine, Ernst-Moritz-University, Greifswald, Germany
  5. 5Exocrine Pancreas Research Unit, Hospital Universitari Vall d'Hebron, Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, CIBEREHD, Barcelona, Spain
  6. 6Osaka University of Pharmaceutical Sciences, Osaka, Japan
  7. 7Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain
  1. Correspondence to Dr Francisco X Real, Cancer Cell Biology Programme, Centro Nacional de Investigaciones Oncológicas (CNIO), Melchor Fernández Almagro, 3, Madrid 28029, Spain; preal{at}cnio.es

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.

  • Pancreatic Function
  • Pancreatitis
  • Pancreatic Secretion
  • Cell Signalling

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