title: Role of ErbB2 in the prostaglandin E₂-induced enhancement of the mitogenic response to epidermal growth factor in cultured hepatocytes.
abstract: Prostaglandin E(2) (PGE(2)) enhances the mitogenic response to epidermal growth factor (EGF) in hepatocytes, but the underlying mechanisms are not clear. We previously observed that PGE(2) upregulates EGF-induced signalling in the MEK/ERK and PI3K/Akt pathways in hepatocytes. Other investigations have indicated that ErbB2 enhances the mitogenic effect of EGF in these cells. In the present study we found that treatment with PGE(2) increased ErbB2 and decreased ErbB3 expression at both the mRNA and protein level in cultured rat hepatocytes. Silencing of the ErbB2 expression with specific siRNA blocked the stimulation by PGE(2) and EGF of cyclin D1 expression and DNA synthesis. Both EGF and PGE(2) increased the expression of ERK and Akt, but while the effect of EGF was inhibited by ErbB2-directed siRNA, this did not affect the PGE(2)-induced upregulation of ERK and Akt. These data suggest that PGE(2) can enhance the mitogenic effect of EGF both by increasing ErbB2 expression and by ErbB2-independent mechanisms.
authors.affiliation: Department of Pharmacology, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo and Oslo University Hospital, Oslo, Norway. john.odegard@medisin.uio.no
authors.forename: John
authors.initials: J
authors.lastname: Ødegård
authors.forename: Monica
authors.initials: M
authors.lastname: Aasrum
authors.forename: Ingun H
authors.initials: IH
authors.lastname: Tveteraas
authors.forename: Suman P
authors.initials: SP
authors.lastname: Bharath
authors.forename: Dagny
authors.initials: D
authors.lastname: Sandnes
authors.forename: Thoralf
authors.initials: T
authors.lastname: Christoffersen
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D015232:Dinoprostone / Q000494:pharmacology*; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008934:Mitogens / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000502:physiology*; D015854:Up-Regulation
chemical_list: D015232:Dinoprostone; D004815:Epidermal Growth Factor; D008934:Mitogens; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; C483804:Erbb2 protein, rat