title: Mnk1 is a novel acinar cell-specific kinase required for exocrine pancreatic secretion and response to pancreatitis in mice.
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.
  
  
  METHODS
  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.
authors.affiliation: Epithelial Carcinogenesis Group, Spanish National Cancer Research Center-CNIO, Madrid, Spain.
authors.forename: Jaroslaw
authors.initials: J
authors.lastname: Cendrowski
authors.affiliation: Epithelial Carcinogenesis Group, Spanish National Cancer Research Center-CNIO, Madrid, Spain.
authors.forename: Víctor J Sánchez-Arévalo
authors.initials: VJ
authors.lastname: Lobo
authors.affiliation: Department of Medicine A, University Medicine, Ernst-Moritz-Arndt University, Greifswald, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Sendler
authors.affiliation: Servei d'Anatomia Patològica, Hospital Mútua Terrassa, Barcelona, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Salas
authors.affiliation: Institute of Radiology, University Medicine, Ernst-Moritz-University, Greifswald, Germany.
authors.forename: Jens-Peter
authors.initials: JP
authors.lastname: Kühn
authors.affiliation: Exocrine Pancreas Research Unit, Hospital Universitari Vall d'Hebron, Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, CIBEREHD, Barcelona, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Molero
authors.affiliation: Osaka University of Pharmaceutical Sciences, Osaka, Japan.
authors.forename: Rikiro
authors.initials: R
authors.lastname: Fukunaga
authors.affiliation: Department of Medicine A, University Medicine, Ernst-Moritz-Arndt University, Greifswald, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Mayerle
authors.affiliation: Department of Medicine A, University Medicine, Ernst-Moritz-Arndt University, Greifswald, Germany.
authors.forename: Markus M
authors.initials: MM
authors.lastname: Lerch
authors.affiliation: Epithelial Carcinogenesis Group, Spanish National Cancer Research Center-CNIO, Madrid, Spain Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Francisco X
authors.initials: FX
authors.lastname: Real
mesh_terms: D061354:Acinar Cells / Q000166:cytology / Q000201:enzymology*; D000681:Amylases / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation; D002108:Ceruletide; D049448:Cholangiopancreatography, Magnetic Resonance; D015536:Down-Regulation; D004789:Enzyme Activation; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism; D018390:Gene Targeting; D018869:Heat-Shock Response / Q000502:physiology; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D046790:Pancreas, Exocrine / Q000378:metabolism*; D010195:Pancreatitis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D014362:Trypsinogen / Q000378:metabolism
chemical_list: D039561:Eukaryotic Initiation Factor-4E; D014157:Transcription Factors; C062602:transcription factor PTF1; D002108:Ceruletide; D014362:Trypsinogen; C106281:Mknk1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases; D000681:Amylases
keywords: Cell Signalling; Pancreatic Function; Pancreatic Secretion; Pancreatitis