Polycystin-1 regulates amphiregulin expression through CREB and AP1 signalling: Implications in ADPKD cell proliferation

Gianluca Aguiari, Fabiana Bizzarri, Anna Bonon, Alessandra Mangolini, Eros Magri, Massimo Pedriali, Patrizia Querzoli, Stefan Somlo, Peter C Harris, Luigi Catizone, Laura Del Senno

Research output: Contribution to journalArticle

27 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1267-1282
Number of pages16
JournalJournal of Molecular Medicine
Volume90
Issue number11
DOIs
StatePublished - Nov 2012

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Keywords

  • ADPKD
  • Amphiregulin
  • AP1
  • cAMP
  • Cell proliferation
  • CREB

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery
  • Genetics(clinical)

Cite this

Aguiari, G., Bizzarri, F., Bonon, A., Mangolini, A., Magri, E., Pedriali, M., Querzoli, P., Somlo, S., Harris, P. C., Catizone, L., & Del Senno, L. (2012). Polycystin-1 regulates amphiregulin expression through CREB and AP1 signalling: Implications in ADPKD cell proliferation. Journal of Molecular Medicine, 90(11), 1267-1282. https://doi.org/10.1007/s00109-012-0902-3