Transgenic overexpression of amphiregulin induces a mitogenic response selectively in pancreatic duct cells

Gastroenterology. 2002 Jun;122(7):1898-912. doi: 10.1053/gast.2002.33594.


Background & aims: The epidermal growth factor (EGF) receptor family and the corresponding ligands are frequently overexpressed in pancreatic cancer. To compare the biological effects of transforming growth factor (TGF)-alpha and amphiregulin (AR) on growth and differentiation of the exocrine pancreas, we have generated transgenic mice overexpressing AR under control of the elastase promoter.

Methods: Two independently generated transgenic mouse lines overexpress 50-, 43-, 28-, 26-, and 16-kilodalton AR forms in the pancreas.

Results: Morphologic and immunohistochemical examinations suggest that small intralobular duct and centro-acinar cells proliferate in response to AR in these mice. AR transgenic mice display increased Ras, Erk1/2, cyclin D/CDK4, and cyclin E/CDK2 activity and G1/S progression in pancreatic duct cells. In contrast to TGF-alpha transgenic mice, AR neither induced tubular complex formation nor elicited a strong fibrogenic response. AR induced a slight induction of ErbB2 on duct cells, whereas TGF-alpha resulted in overexpression of the EGF receptor in cells within tubular complexes. Furthermore, AR and TGF-alpha displayed different effects on differentiation of isolated acini in vitro comparable to the situation in vivo.

Conclusions: These data suggest that AR induces a mitogenic response selectively in small duct cells through activation of Ras, CDK2, and CDK4, respectively. The closely related EGF receptor ligands, AR and TGF-alpha, display different biological effects when overexpressed in the exocrine pancreas in vivo.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amphiregulin
  • Animals
  • Cell Cycle / drug effects
  • Cell Differentiation / drug effects
  • EGF Family of Proteins
  • ErbB Receptors / genetics
  • Fluorescent Antibody Technique
  • Gene Expression
  • Glycoproteins / genetics
  • Glycoproteins / metabolism
  • Glycoproteins / pharmacology*
  • Growth Substances / genetics
  • Growth Substances / metabolism
  • Growth Substances / pharmacology*
  • Intercellular Signaling Peptides and Proteins*
  • Mice
  • Mice, Transgenic / genetics
  • Microscopy, Electron
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases / metabolism
  • Mitogens / pharmacology*
  • Pancreatic Ducts / cytology*
  • Pancreatic Ducts / drug effects*
  • Pancreatic Ducts / metabolism
  • Pancreatic Ducts / ultrastructure
  • Receptor, ErbB-2 / genetics
  • Reference Values
  • Staining and Labeling
  • Transforming Growth Factor alpha / genetics
  • Transforming Growth Factor alpha / pharmacology
  • Up-Regulation
  • ras Proteins / metabolism


  • Amphiregulin
  • Areg protein, mouse
  • EGF Family of Proteins
  • Glycoproteins
  • Growth Substances
  • Intercellular Signaling Peptides and Proteins
  • Mitogens
  • Transforming Growth Factor alpha
  • ErbB Receptors
  • Receptor, ErbB-2
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • ras Proteins