Expression of the Notch signaling pathway and effect on exocrine cell proliferation in adult rat pancreas.
When pancreatic tissue is injured after duct obstruction, acinoductal metaplasia is observed. Similar metaplastic changes occur when exocrine pancreatic cells are isolated and cultured. We demonstrate that under these experimental conditions the exocrine acinar cells lose their differentiated characteristics: expression of the acinar transcription factors p48/Ptf1alpha and Mist1 is decreased or lost, whereas expression of the embryonic transcription factor Pdx1 is increased. The receptors Notch1 and Notch2, members of the DSL family of Notch ligands, and the target genes in the Notch-signaling pathway Hes1, Hey1, and Hey2 become strongly up-regulated. We noted also reduced expression of Sel1L, a Notch repressor that is normally highly expressed in exocrine pancreas. Stimulation of Notch by its ligand Jagged1 diminished the proliferation of cultured metaplastic exocrine cells. Chemical inhibition of Notch signaling resulted in increased proliferation and induction of the cell-cycle regulator p21Cip1. This effect seems to be Hes1-independent and mainly coincides with decreased Hey1 and Hey2 mRNA expression. In conclusion, we demonstrate that during acinoductal metaplasia the Notch-signaling pathway is activated concomitantly with changes in transcription factor expression of pancreatic acinar cells. In addition, we show that Notch signaling is implicated in the suppression of proliferation of these metaplastic exocrine cells. The latter may be important in protection from neoplastic transformation.
Rooman
Ilse
I
Cell Differentiation Unit-Diabetes Research Center, Vrije Universiteit Brussel, Laarbeeklaan 103, B-1090 Brussels, Belgium. irooman@vub.ac.be
De Medts
Nele
N
Baeyens
Luc
L
Lardon
Jessy
J
De Breuck
Saskia
S
Heimberg
Harry
H
Bouwens
Luc
L
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D008026:Ligation; D008297:Male; D008679:Metaplasia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D046790:Pancreas, Exocrine / Q000737:chemistry / Q000378:metabolism / Q000473:pathology*; D010183:Pancreatic Ducts / Q000737:chemistry / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D017208:Rats, Wistar; D051880:Receptors, Notch / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D015534:Trans-Activators / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D000072056:Transcription Factor HES-1; D014157:Transcription Factors / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
D051792:Basic Helix-Loop-Helix Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018398:Homeodomain Proteins; D051880:Receptors, Notch; D012097:Repressor Proteins; D015534:Trans-Activators; D000072056:Transcription Factor HES-1; D014157:Transcription Factors; C105074:Bhlha15 protein, rat; C405694:Hairy, HRT1 protein; C489735:Hes1 protein, rat; C084010:pancreatic and duodenal homeobox 1 protein; C062602:transcription factor PTF1