c-Jun/AP-1 is required for CCK-induced pancreatic acinar cell dedifferentiation and DNA synthesis in vitro

Am J Physiol Gastrointest Liver Physiol. 2012 Jun 15;302(12):G1381-96. doi: 10.1152/ajpgi.00129.2010. Epub 2012 Mar 29.


Endogenous CCK plays an important role in pancreatic regeneration after pancreatitis. We used primary culture of mouse pancreatic acinar cells to evaluate the effect of CCK on acinar cell morphology and gene expression and to determine signaling pathways required for proliferation of acinar cells in vitro. Over 4 days in culture, cells grew out from acini and formed patches of monolayer, which displayed a reduced expression of acinar cell markers including digestive enzymes and Mist1 and an increased expression of ductal and embryonic markers, including cytokeratin 7, β-catenin, E-cadherin, pdx-1, and nestin. There was no appearance of stellate cell markers. CCK enhanced cellular spreading, DNA synthesis, and cyclin D1 expression. When signaling pathways were evaluated, CCK stimulation increased c-Jun expression, JNK and ERK activity, and AP-1 activation. Chemical inhibitors of JNK and ERK pathways, dominant-negative JNK and c-Jun, and c-Jun shRNA significantly inhibited CCK-induced DNA synthesis, CCK-induced AP-1 activation, and cyclin D1 expression. Furthermore, dominant-negative c-Jun reduced the increased expression of β-catenin and the decreased expression of amylase during culture. These results show that MAPK/c-Jun/AP-1 pathway plays an important role in pancreatic acinar cell dedifferentiation and proliferation in culture. Monolayer culture can serve as a model to study acinar cell proliferation similar to regeneration after pancreatitis in vivo.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acinar Cells / drug effects
  • Acinar Cells / metabolism*
  • Amylases / metabolism
  • Animals
  • Cadherins / metabolism
  • Cell Dedifferentiation / drug effects
  • Cell Dedifferentiation / physiology*
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Cholecystokinin / pharmacology*
  • Cyclin D1 / metabolism
  • DNA Replication / drug effects
  • DNA Replication / physiology*
  • Mice
  • Pancreas / drug effects
  • Pancreas / metabolism
  • Proto-Oncogene Proteins c-jun / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Transcription Factor AP-1 / metabolism*
  • beta Catenin / metabolism


  • Cadherins
  • Proto-Oncogene Proteins c-jun
  • Transcription Factor AP-1
  • beta Catenin
  • Cyclin D1
  • Cholecystokinin
  • Amylases