title: ErbB3(80 kDa), a nuclear variant of the ErbB3 receptor, binds to the Cyclin D1 promoter to activate cell proliferation but is negatively controlled by p14ARF.
abstract: EGFR family members are tyrosine kinase transmembrane receptors that, in response to specific extracellular ligands, activate cytoplasmic pathways involved in cell proliferation, migration and differentiation. More recently, a pivotal role for EGF receptors has emerged, through the description of their nuclear localization.We report here the characterization of a nuclear variant of the kinase-defective ErbB3 receptor, ErbB3(80 kDa), spanning the intracytoplasmic domain of the receptor. We assessed the putative transcriptional functions of ErbB3(80 KDa) in cancer cells, through the regulation of the proliferative Cyclin D1 gene, an already known target of the ErbB3 cytoplasmic signaling. We demonstrate here that the binding of ErbB3(80 KDa) on the promoter activates Cyclin D1 transcription and subsequent protein expression, leading to an increased cell proliferation. This mechanism can be balanced in response to the ectopic expression of the tumor suppressor p14ARF that physically interacts with ErbB3(100 kDa) and sequesters it into nucleoli. Our data also show that ErbB3(80 kDa) increases the transcription of proliferative genes even though the cytoplasmic pathways are not activated. This nuclear ErbB3 pathway and the target genes concerned need to be further studied. Indeed, such mechanism could explain the tumor relapse observed in response to treatments aimed at blocking the receptor activation in response to ligand binding.
authors.affiliation: University of Poitiers, PBS, 40 Av Recteur Pineau, 86022, Poitiers cedex, CNRS UMR 6187, IPBC, France.
authors.forename: Laëtitia
authors.initials: L
authors.lastname: Andrique
authors.forename: Dominique
authors.initials: D
authors.lastname: Fauvin
authors.forename: Mahmoud
authors.initials: M
authors.lastname: El Maassarani
authors.forename: Hélène
authors.initials: H
authors.lastname: Colasson
authors.forename: Brigitte
authors.initials: B
authors.lastname: Vannier
authors.forename: Paule
authors.initials: P
authors.lastname: Séité
mesh_terms: D000595:Amino Acid Sequence; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D049410:Luciferases, Renilla / Q000096:biosynthesis / Q000235:genetics; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D020033:Protein Isoforms / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015533:Transcriptional Activation; D025803:Tumor Suppressor Protein p14ARF / Q000378:metabolism / Q000502:physiology*; D054462:p21-Activated Kinases / Q000378:metabolism
chemical_list: C530104:CCND1 protein, human; D020033:Protein Isoforms; D011993:Recombinant Fusion Proteins; D025803:Tumor Suppressor Protein p14ARF; C485184:enhanced green fluorescent protein; D019938:Cyclin D1; D049452:Green Fluorescent Proteins; D049410:Luciferases, Renilla; D020893:Receptor, ErbB-3; C515903:PAK1 protein, human; D054462:p21-Activated Kinases