title: Attenuation of epidermal growth factor (EGF) signaling by growth hormone (GH).
abstract: Transgenic mice overexpressing growth hormone (GH) show increased hepatic protein content of the epidermal growth factor receptor (EGFR), which is broadly associated with cell proliferation and oncogenesis. However, chronically elevated levels of GH result in desensitization of STAT-mediated EGF signal and similar response of ERK1/2 and AKT signaling to EGF compared to normal mice. To ascertain the mechanisms involved in GH attenuation of EGF signaling and the consequences on cell cycle promotion, phosphorylation of signaling mediators was studied at different time points after EGF stimulation, and induction of proteins involved in cell cycle progression was assessed in normal and GH-overexpressing transgenic mice. Results from kinetic studies confirmed the absence of STAT3 and 5 activation and comparable levels of ERK1/2 phosphorylation upon EGF stimulation, which was associated with diminished or similar induction of c-MYC, c-FOS, c-JUN, CYCLIN D1 and CYCLIN E in transgenic compared to normal mice. Accordingly, kinetics of EGF-induced c-SRC and EGFR phosphorylation at activating residues demonstrated that activation of these proteins was lower in the transgenic mice with respect to normal animals. In turn, EGFR phosphorylation at serine 1046/1047, which is implicated in the negative regulation of the receptor, was increased in the liver of GH-overexpressing transgenic mice both in basal conditions and upon EGF stimulus. Increased basal phosphorylation and activation of the p38-mitogen-activated protein kinase might account for increased Ser 1046/1047 EGFR. Hyperphosphorylation of EGFR at serine residues would represent a compensatory mechanism triggered by chronically elevated levels of GH to mitigate the proliferative response induced by EGF.
authors.affiliation: Instituto de Química y Fisicoquímica Biológicas (UBA-CONICET)Facultad de Farmacia y Bioquímica, Buenos Aires, Argentina lgonzalez@qb.ffyb.uba.ar.
authors.forename: Lorena
authors.initials: L
authors.lastname: González
authors.affiliation: Instituto de Química y Fisicoquímica Biológicas (UBA-CONICET)Facultad de Farmacia y Bioquímica, Buenos Aires, Argentina.
authors.forename: Johanna G
authors.initials: JG
authors.lastname: Miquet
authors.affiliation: Instituto de Química y Fisicoquímica Biológicas (UBA-CONICET)Facultad de Farmacia y Bioquímica, Buenos Aires, Argentina.
authors.forename: Pablo E
authors.initials: PE
authors.lastname: Irene
authors.affiliation: Instituto de Química y Fisicoquímica Biológicas (UBA-CONICET)Facultad de Farmacia y Bioquímica, Buenos Aires, Argentina.
authors.forename: M Eugenia
authors.initials: ME
authors.lastname: Díaz
authors.affiliation: Instituto de Biología y Medicina ExperimentalCONICET, Ciudad de Buenos Aires, Argentina.
authors.forename: Soledad P
authors.initials: SP
authors.lastname: Rossi
authors.affiliation: Instituto de Química y Fisicoquímica Biológicas (UBA-CONICET)Facultad de Farmacia y Bioquímica, Buenos Aires, Argentina.
authors.forename: Ana I
authors.initials: AI
authors.lastname: Sotelo
authors.affiliation: Instituto de Biología y Medicina ExperimentalCONICET, Ciudad de Buenos Aires, Argentina.
authors.forename: Mónica B
authors.initials: MB
authors.lastname: Frungieri
authors.affiliation: Departments of Internal Medicine and PhysiologyGeriatrics Research, School of Medicine, Southern Illinois University, Springfield, Illinois, USA.
authors.forename: Cristal M
authors.initials: CM
authors.lastname: Hill
authors.affiliation: Departments of Internal Medicine and PhysiologyGeriatrics Research, School of Medicine, Southern Illinois University, Springfield, Illinois, USA.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Bartke
authors.affiliation: Instituto de Química y Fisicoquímica Biológicas (UBA-CONICET)Facultad de Farmacia y Bioquímica, Buenos Aires, Argentina.
authors.forename: Daniel
authors.initials: D
authors.lastname: Turyn
mesh_terms: D000818:Animals; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology*; D016391:Genes, src / Q000235:genetics / Q000502:physiology; D013006:Growth Hormone / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D050791:STAT Transcription Factors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D050791:STAT Transcription Factors; D004815:Epidermal Growth Factor; D013006:Growth Hormone; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Ser 1046/1047 EGFR phosphorylation; epidermal growth factor (EGF); growth hormone (GH); liver; signal transduction; transgenic mice