Mice lacking the transcription factor Mist1 exhibit an altered stress response and increased sensitivity to caerulein-induced pancreatitis.
Several animal models have been developed to investigate the pathobiology of pancreatitis, but few studies have examined the effects that altered pancreatic gene expression have in these models. In this study, the sensitivity to secretagogue-induced pancreatitis was examined in a mouse line that has an altered acinar cell environment due to the targeted deletion of Mist1. Mist1 is an exocrine specific transcription factor important for the complete differentiation and function of pancreatic acinar cells. Mice lacking the Mist1 gene [Mist1 knockout (KO) mice] exhibit cellular disorganization and functional defects in the exocrine pancreas but no gross morphological defects. Following the induction of pancreatitis with caerulein, a CCK analog, we observed elevated serum amylase levels, necrosis, and tissue damage in Mist1 KO mice, indicating increased pancreatic damage. There was also a delay in the regeneration of acinar tissue in Mist1 KO animals. Molecular profiling revealed an altered activation of stress response genes in Mist1 KO pancreatic tissue compared with wild-type (WT) tissue following the induction of pancreatitis. In particular, Western blot analysis for activating transcription factor 3 and phosphorylated eukaryotic initiation factor 2alpha (eIF2alpha), mediators of endoplasmic reticulum (ER) stress, indicated limited activation of this pathway in Mist1 KO animals compared with WT controls. Conversely, Mist1 KO pancreatic tissue exhibits increased expression of growth arrest and DNA damage inducible 34 protein, an inhibitor of eIF2alpha phosphorylation, before and after the induction of pancreatitis. These finding suggest that activation of the ER stress pathway is a protective event in the progression of pancreatitis and highlight the Mist1 KO mouse line as an important new model for studying the molecular events that contribute to the sensitivity to pancreatic injury.
Kowalik
Agnes S
AS
Department of Physiology, The University of Western Ontario, London, Ontario, Canada.
Johnson
Charis L
CL
Chadi
Sami A
SA
Weston
Jacqueline Y
JY
Fazio
Elena N
EN
Pin
Christopher L
CL
D051700:Activating Transcription Factor 3 / Q000235:genetics / Q000378:metabolism; D000208:Acute Disease; D000681:Amylases / Q000097:blood; D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D051792:Basic Helix-Loop-Helix Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D002108:Ceruletide; D002766:Cholecystokinin / Q000378:metabolism / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D015852:Eukaryotic Initiation Factor-2 / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046790:Pancreas, Exocrine / Q000378:metabolism* / Q000473:pathology; D010195:Pancreatitis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D054645:Protein Phosphatase 1; D012333:RNA, Messenger / Q000378:metabolism; D012038:Regeneration; D012720:Severity of Illness Index; D013312:Stress, Physiological / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D013997:Time Factors
D051700:Activating Transcription Factor 3; D000681:Amylases; D000943:Antigens, Differentiation; D051792:Basic Helix-Loop-Helix Proteins; D018797:Cell Cycle Proteins; D002108:Ceruletide; D002766:Cholecystokinin; D015852:Eukaryotic Initiation Factor-2; D017874:Immediate-Early Proteins; D054645:Protein Phosphatase 1; D012333:RNA, Messenger; C103002:Atf3 protein, mouse; C491312:Bhlha15 protein, mouse; C513256:Ppp1r15a protein, mouse