title: Polycystin-1 regulates amphiregulin expression through CREB and AP1 signalling: implications in ADPKD cell proliferation.
abstract: In autosomal dominant polycystic kidney disease (ADPKD), renal cyst development and enlargement, as well as cell growth, are associated with alterations in several pathways, including cAMP and activator protein 1 (AP1) signalling. However, the precise mechanism by which these molecules stimulate cell proliferation is not yet fully understood. We now show by microarray analysis, luciferase assay, mutagenesis, and chromatin immunoprecipitation that CREB and AP1 contribute to increased expression of the amphiregulin gene, which codifies for an epidermal growth factor-like peptide, in ADPKD cystic cells, thereby promoting their cell growth. Increased amphiregulin (AR) expression was associated with abnormal cell proliferation in both PKD1-depleted and -mutated epithelial cells, as well as primary cystic cell lines isolated from ADPKD kidney tissues. Consistently, normal AR expression and proliferation were re-established in cystic cells by the expression of a mouse full-length PC1. Finally, we show that anti-AR antibodies and inhibitors of AP1 are able to reduce cell proliferation in cystic cells by reducing AR expression and EGFR activity. AR can therefore be considered as one of the key activators of the growth of human ADPKD cystic cells and thus a new potential therapeutic target.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Ferrara, via Fossato di Mortara, 74, 44121 Ferrara, Italy. dsn@unife.it
authors.forename: Gianluca
authors.initials: G
authors.lastname: Aguiari
authors.forename: Fabiana
authors.initials: F
authors.lastname: Bizzarri
authors.forename: Anna
authors.initials: A
authors.lastname: Bonon
authors.forename: Alessandra
authors.initials: A
authors.lastname: Mangolini
authors.forename: Eros
authors.initials: E
authors.lastname: Magri
authors.forename: Massimo
authors.initials: M
authors.lastname: Pedriali
authors.forename: Patrizia
authors.initials: P
authors.lastname: Querzoli
authors.forename: Stefan
authors.initials: S
authors.lastname: Somlo
authors.forename: Peter C
authors.initials: PC
authors.lastname: Harris
authors.forename: Luigi
authors.initials: L
authors.lastname: Catizone
authors.forename: Laura
authors.initials: L
authors.lastname: Del Senno
mesh_terms: D066258:Amphiregulin; D000818:Animals; D049109:Cell Proliferation; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000096:biosynthesis*; D066255:EGF Family of Proteins; D020868:Gene Silencing; D006023:Glycoproteins / Q000096:biosynthesis* / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis* / Q000378:metabolism; D051379:Mice; D016296:Mutagenesis; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D016891:Polycystic Kidney, Autosomal Dominant / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D050396:TRPP Cation Channels / Q000378:metabolism / Q000502:physiology*; D018808:Transcription Factor AP-1 / Q000096:biosynthesis*
chemical_list: D066258:Amphiregulin; D000242:Cyclic AMP; D017362:Cyclic AMP Response Element-Binding Protein; D066255:EGF Family of Proteins; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D050396:TRPP Cation Channels; D018808:Transcription Factor AP-1; C587848:AREG protein, human; C587849:Areg protein, mouse; C115163:CREB1 protein, human; C492004:Creb1 protein, mouse