The EGF receptor is required for efficient liver regeneration.
Mice lacking the EGF receptor (EGFR) die between midgestation and postnatal day 20 with various defects in neural and epithelial organs. Here, we generated mice carrying a floxed EGFR allele to inactivate the EGFR in fetal and adult liver. Perinatal deletion of EGFR in hepatocytes resulted in decreased body weight, whereas deletion in the adult liver did not affect body mass. Although liver function was not affected, after partial hepatectomy mice lacking EGFR in the liver showed increased mortality accompanied by increased levels of serum transaminases indicating liver damage. Liver regeneration was delayed in the mutants because of reduced hepatocyte proliferation. Analysis of cell cycle progression in EGFR-deficient livers indicated a defective G(1)-S phase entry with delayed transcriptional activation and reduced protein expression of cyclin D1 followed by reduced cdk2 and cdk1 expression. Impaired liver regeneration was accompanied by compensatory up-regulation of TNFalpha in the serum and prolonged activation of c-Jun. Moreover, p38alpha and NF-kappaB activation was reduced in regenerating mutant livers, indicating an impaired stress response after hepatectomy. Our studies demonstrate that EGFR is a critical regulator of hepatocyte proliferation in the initial phases of liver regeneration.
Natarajan
Anuradha
A
Department of Dermatology, Division of Immunology, Allergy, and Infectious Diseases, and Institute for Cancer Research, Department of Medicine 1, Vienna Competence Center, Medical University of Vienna, Lazarettgasse 19, A-1090 Vienna, Austria.
Wagner
Bettina
B
Sibilia
Maria
M
D000483:Alleles; D000818:Animals; D002453:Cell Cycle; D049109:Cell Proliferation; D016207:Cytokines / Q000096:biosynthesis; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D018390:Gene Targeting; D006498:Hepatectomy; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000201:enzymology; D008115:Liver Regeneration / Q000502:physiology*; D051379:Mice; D015398:Signal Transduction
D016207:Cytokines; D066246:ErbB Receptors