title: Aberrant polycystin-1 expression results in modification of activator protein-1 activity, whereas Wnt signaling remains unaffected.
abstract: Polycystin-1, the polycystic kidney disease 1 gene product, has been implicated in several signaling complexes that are known to regulate essential cellular functions. We investigated the role of polycystin-1 in Wnt signaling and activator protein-1 (AP-1) activation. To this aim, a membrane-targeted construct encoding the conserved C-terminal region of mouse polycystin-1 reported to mediate signal transduction activity was expressed in human embryonic and renal epithelial cells. To ensure specificity and minimal cotransfection effects, we focused our study on the endogenous proteins that actually transduce the signals, beta-catenin and T-cell factor/lymphoid-enhancing factor for Wnt signaling and (phosphorylated) c-Jun, ATF2, and c-Fos for AP-1. Our data indicate that the C-terminal region of polycystin-1 activates AP-1 by inducing phosphorylation and expression of at least c-Jun and ATF2, whereas c-Fos was not affected. Under our experimental conditions, polycystin-1 did not modulate Wnt signaling. AP-1 activity was aberrant in human autosomal dominant polycystic kidney disease (ADPKD) renal cystic epithelial cells and in renal epithelial cells expressing transgenic full-length polycystin-1, resulting in decreased Jun-ATF and increased Jun-Fos activity, whereas Wnt signaling remained unaffected. Since our data indicate that aberrant polycystin-1 expression results in altered AP-1 activity, polycystin-1 may be required for adequate AP-1 activity.
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden 2333 AL, The Netherlands.
authors.forename: Ngoc Hang
authors.initials: NH
authors.lastname: Le
authors.forename: Paola
authors.initials: P
authors.lastname: van der Bent
authors.forename: Gerwin
authors.initials: G
authors.lastname: Huls
authors.forename: Marc
authors.initials: M
authors.lastname: van de Wetering
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Loghman-Adham
authors.forename: Albert C M
authors.initials: AC
authors.lastname: Ong
authors.forename: James P
authors.initials: JP
authors.lastname: Calvet
authors.forename: Hans
authors.initials: H
authors.lastname: Clevers
authors.forename: Martijn H
authors.initials: MH
authors.lastname: Breuning
authors.forename: Hans
authors.initials: H
authors.lastname: van Dam
authors.forename: Dorien J M
authors.initials: DJ
authors.lastname: Peters
mesh_terms: D051698:Activating Transcription Factor 2; D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004285:Dogs; D006801:Humans; D007668:Kidney / Q000166:cytology; D051379:Mice; D010766:Phosphorylation; D014176:Protein Biosynthesis; D011506:Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism / Q000502:physiology*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D050396:TRPP Cation Channels; D015534:Trans-Activators / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D019076:Transgenes / Q000235:genetics; D051153:Wnt Proteins; D051176:beta Catenin
chemical_list: D051698:Activating Transcription Factor 2; D017362:Cyclic AMP Response Element-Binding Protein; D003598:Cytoskeletal Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D011993:Recombinant Fusion Proteins; D050396:TRPP Cation Channels; D015534:Trans-Activators; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin; C497105:ATF2 protein, human; C497106:Atf2 protein, mouse; C497107:Atf2 protein, rat; C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; C495268:Ctnnb1 protein, rat