title: EGFR is involved in control of gastric cell proliferation through activation of MAPK and Src signalling pathways in early-weaned rats.
abstract: OBJECTIVE
  Early weaning (EW) increases proliferation of the gastric epithelium in parallel with higher expression of transforming growth factor alpha and its receptor epidermal growth factor receptor (EGFR). The primary objective of the present study was to examine involvement of EGFR signalling in regulating mucosal cell proliferation during the early weaning period.
  
  
  METHODS
  Fifteen-day-old rats were split into two groups: suckling (control) and EW, in which pups were separated from the dam. Animals were killed daily until the 18th day, 3 days after onset of treatment. To investigate the role of EGFR in proliferation control, EW pups were injected with AG1478, an EGFR inhibitor; signalling molecules, proliferative indices and cell cycle-related proteins were evaluated.
  
  
  RESULTS
  EW increased ERK1/2 and Src phosphorylation at 17 days, but p-Akt levels were unchanged. Moreover, at 17 days, AG1478 administration impaired ERK phosphorylation, whereas p-Src and p-Akt were not altered. AG1478 treatment reduced mitotic and DNA synthesis indices, which were determined on HE-stained and BrdU-labelled sections. Finally, AG1478 injection decreased p21 levels in the gastric mucosa at 17 days, while no changes were detected in p27, cyclin E, CDK2, cyclin D1 and CDK4 concentrations.
  
  
  CONCLUSIONS
  EGFR is part of the mechanism that regulates cell proliferation in rat gastric mucosa during early weaning. We suggest that such responses might depend on activation of MAPK and/or Src signalling pathways and regulation of p21 levels.
authors.affiliation: Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil.
authors.forename: L H
authors.initials: LH
authors.lastname: Osaki
authors.forename: P M
authors.initials: PM
authors.lastname: Figueiredo
authors.forename: E P
authors.initials: EP
authors.lastname: Alvares
authors.forename: P
authors.initials: P
authors.lastname: Gama
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000378:metabolism; D019927:Cyclin E / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D005753:Gastric Mucosa / Q000166:cytology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D008938:Mitosis; D010766:Phosphorylation; D011799:Quinazolines; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D020032:Tyrphostins / Q000494:pharmacology; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D019927:Cyclin E; D050759:Cyclin-Dependent Kinase Inhibitor p21; D011799:Quinazolines; D020032:Tyrphostins; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; C101044:RTKI cpd; D066246:ErbB Receptors; D019061:src-Family Kinases; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3