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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.

SUBMITTER: Aguiari G

PROVIDER: S-EPMC4028691 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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

Aguiari Gianluca G Bizzarri Fabiana F Bonon Anna A Mangolini Alessandra A Magri Eros E Pedriali Massimo M Querzoli Patrizia P Somlo Stefan S Harris Peter C PC Catizone Luigi L Del Senno Laura L

Journal of molecular medicine (Berlin, Germany) 20120509 11

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 o ...[more]

PMID: 22570239

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Project description:MicroRNAs (miRNAs) regulate many basic aspects of cell biology including neuronal plasticity, but little is known of their roles in drug addiction. Extended access to cocaine can trigger the emergence of compulsive drug-seeking behaviors, but molecular mechanisms regulating this process remain unclear. Here we report that microRNA-212 (miR-212) is upregulated in the dorsal striatum of rats with extended access to cocaine. Striatal overexpression of miR-212 decreases, whereas its inhibition increases cocaine intake in rats with extended but not restricted drug access, suggesting that miR-212 serves as a protective factor against the development of compulsive drug seeking. The transcription factor CREB (cAMP response element-binding protein) is considered a core regulator of cocaine reward. We show that miR-212 controls responsiveness to cocaine by dramatically amplifying striatal CREB signaling. This action occurs through miR-212-enhanced Raf-1 activity, resulting in adenylyl cyclase sensitization and increased expression of the essential CREB co-activator TORC (Transducer of Regulated CREB; also known as CRTC). Our findings suggest that striatal miR-212 signaling plays a key role in vulnerability to addiction, and that noncoding RNAs such as the miRNAs may serve as novel targets for the development of anti-addiction therapeutics. To identify potential targets for miR-212, we transfected cells with a vector to overexpress miR-212 or an empty vector. We then analyzed profiled gene expression using Affymetrix arrays. Human Affymetrix Study: Cells were transfected with a vector to overexpress miR-212 or an empty vector. We then analyzed profiled gene expression using Affymetrix arrays. The complete, unfiltered set of signal intensity data for Samples miR-212 and pMIF, including miR-212/pMIF ratios, are in the supplementary file at the foot of the record. Probes excluded from analysis (pMIF intensity <100) are indicated in the supplementary file by a no in the far-right column, 'Passed data filtering and included in analysis: no/yes'. Probes that were included in the analyses (pMIF intensity >100) are indicated in the supplementary file by a yes in the 'Passed data filtering and included in analysis: no/yes' column. Rat miRNA Study: Rats were permitted access to intravenous cocaine self-administration (0.5 mg/kg/infusion) for 7 consecutive days during restricted (1-h) or extended (6-h) daily sessions. Control rats remained coaine-naïve throughout. 24-h after the last session the dorsal striatum from each rats was removed, and RNA extracted for microarray profiling. There was a total of n=6 rats per access condition. RNA from 2 rats per access condition were pooled on to arrays, for a total of 3 arrays per access condition, and 9 arrays in total.

Dataset Information

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

Publications

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

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