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

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

doi:10.1007/s00109-012-0902-3

Cited by 39 publications

(37 citation statements)

References 34 publications

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“…These include members of the EGF family (EGF, TGF-α, heparin-binding EGF, and amphiregulin), HGF and IGF1, and their tyrosine kinase receptors, ErbB1 to ErbB4, MET, and IGF1R, respectively. In most cases, the mechanisms responsible for their upregulation in PKD are not known, but the activation of cAMP response element-binding transcription factor (CREB) and activator protein 1 enhances amphiregulin promoter activity and expression in PC1-mutated cells (125).…”

Section: Growth Factors/receptors As Targets For Pkd Treatmentmentioning

confidence: 99%

Genetic mechanisms and signaling pathways in autosomal dominant polycystic kidney disease

2014

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Recent advances in defining the genetic mechanisms of disease causation and modification in autosomal dominant polycystic kidney disease (ADPKD) have helped to explain some extreme disease manifestations and other phenotypic variability. Studies of the ADPKD proteins, polycystin-1 and -2, and the development and characterization of animal models that better mimic the human disease, have also helped us to understand pathogenesis and facilitated treatment evaluation. In addition, an improved understanding of aberrant downstream pathways in ADPKD, such as proliferation/secretion-related signaling, energy metabolism, and activated macrophages, in which cAMP and calcium changes may play a role, is leading to the identification of therapeutic targets. Finally, results from recent and ongoing preclinical and clinical trials are greatly improving the prospects for available, effective ADPKD treatments.

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Section: Growth Factors/receptors As Targets For Pkd Treatmentmentioning

confidence: 99%

Genetic mechanisms and signaling pathways in autosomal dominant polycystic kidney disease

2014

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“…72 Phosphorylation and inhibition of glycogen synthase kinase 3b 57 and direct phosphorylation and stabilization of b-catenin by PKA 58 enhance Wnt/b-catenin signaling. PKA-dependent upregulation of cAMP response element binding transcription factor, 73 paired box gene 2 (Pax2), 74 and signal transducer and activator of transcription 3 (STAT3) [75][76][77] also contributes to the proliferative phenotype of the cystic epithelium. Pax2 haploinsufficiency inhibits renal cystogenesis in homozygous Pkd1 mutant or cpk mutant mice.…”

Section: Cell Proliferationmentioning

confidence: 99%

Strategies Targeting cAMP Signaling in the Treatment of Polycystic Kidney Disease

Torres

Harris

2014

Journal of the American Society of Nephrology

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Polycystic kidney disease (PKD) is a leading cause of ESRD worldwide. In PKD, excessive cell proliferation and fluid secretion, pathogenic interactions of mutated epithelial cells with an abnormal extracellular matrix and alternatively activated interstitial macrophages, and the disruption of mechanisms controlling tubular diameter contribute to cyst formation. Studies with animal models suggest that several diverse pathophysiologic mechanisms, including dysregulation of intracellular calcium levels and cAMP signaling, mediate these cystogenic mechanisms. This article reviews the evidence implicating calcium and cAMP as central players in a network of signaling pathways underlying the pathogenesis of PKD and considers the therapeutic relevance of treatment strategies targeting cAMP signaling.

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“…These improvements in renal function occur through a reduction in cAMP levels and inhibition of the B-Raf/MEK/ERK pathway, suggesting that AC6 could be a key mediator of cyst formation in ADPKD [31] . In addition, cAMP elevation may activate the cAMP-response element-binding protein, which promotes cell proliferation in an epidermal growth factor receptor (EGFR)-activationdependent manner by stimulating expression of the EGFlike peptide amphiregulin [32] . EGFR signaling is dependent upon a mechanism involving the sequential activation of Ras, Raf-1, MEK and ERK.…”

Section: Calcium Signaling and Cell Proliferation In Adpkd Cellsmentioning

confidence: 99%

Role of calcium in polycystic kidney disease: From signaling to pathology

Mangolini

Stephanis

Aguiari

2016

WJN

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Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited monogenic kidney disease. Characterized by the development and growth of cysts that cause progressive kidney enlargement, it ultimately leads to end-stage renal disease. Approximately 85% of ADPKD cases are caused by mutations in the PKD1 gene, while mutations in the PKD2 gene account for the remaining 15% of cases. The PKD1 gene encodes for polycystin-1 (PC1), a large multi-functional membrane receptor protein able to regulate ion channel complexes, whereas polycystin-2 (PC2), encoded by the PKD2 gene, is an integral membrane protein that functions as a calcium-permeable cation channel, located mainly in the endoplasmic reticulum (ER). In the primary cilia of the epithelial cells, PC1 interacts with PC2 to form a polycystin complex that acts as a mechanosensor, regulating signaling pathways involved in the differentiation of kidney tubular epithelial cells. Despite progress in understanding the function of these proteins, the molecular mechanisms associated with the pathogenesis of ADPKD remain unclear. In this review we discuss how an imbalance between functional PC1 and PC2 proteins may disrupt calcium channel activities in the cilium, plasma membrane and ER, thereby altering intracellular calcium signaling and leading to the aberrant cell proliferation and apoptosis associated with the development and growth of renal cysts. Research in this field could lead to the discovery of new molecules able to rebalance intracellular calcium, thereby normalizing cell proliferation and reducing kidney cyst progression.

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

Cited by 39 publications

References 34 publications

Genetic mechanisms and signaling pathways in autosomal dominant polycystic kidney disease

Genetic mechanisms and signaling pathways in autosomal dominant polycystic kidney disease

Strategies Targeting cAMP Signaling in the Treatment of Polycystic Kidney Disease

Role of calcium in polycystic kidney disease: From signaling to pathology

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