Transgenic overexpression of amphiregulin induces a mitogenic response selectively in pancreatic duct cells.
OBJECTIVE
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.
Wagner
Martin
M
Department of Internal Medicine I, University of Ulm, Germany.
Weber
Christoph K
CK
Bressau
Frank
F
Greten
Florian R
FR
Stagge
Volker
V
Ebert
Matthias
M
Leach
Steven D
SD
Adler
Guido
G
Schmid
Roland M
RM
D066258:Amphiregulin; D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D066255:EGF Family of Proteins; D066246:ErbB Receptors / Q000235:genetics; D005455:Fluorescent Antibody Technique; D015870:Gene Expression; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D006133:Growth Substances / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D036341:Intercellular Signaling Peptides and Proteins; D051379:Mice; D008822:Mice, Transgenic / Q000235:genetics; D008854:Microscopy, Electron; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008934:Mitogens / Q000494:pharmacology*; D010183:Pancreatic Ducts / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D012016:Reference Values; D013194:Staining and Labeling; D016211:Transforming Growth Factor alpha / Q000235:genetics / Q000494:pharmacology; D015854:Up-Regulation; D018631:ras Proteins / Q000378:metabolism
D066258:Amphiregulin; D066255:EGF Family of Proteins; D066246:ErbB Receptors; D006023:Glycoproteins; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D008934:Mitogens; D018719:Erb-b2 Receptor Tyrosine Kinases; D016211:Transforming Growth Factor alpha; D018631:ras Proteins; C587849:Areg protein, mouse