The uroguanylin system and human disease

Rahbi, Hazim; Narayan, Hafid; Jones, Donald J. L.; Ng, Leong L.

doi:10.1042/cs20120021

Cited by 14 publications

(19 citation statements)

References 81 publications

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“…In the intestinal tract, PKG-II is involved in the activation of the cystic fibrosis transmembrane regulator (CFTR) anion channel and chloride channels (ClC), causing the efflux of chloride and bicarbonate. Water is then effluxed into the intestinal lumen [47] . Upon binding of cGMP to the regulatory domain, the auto-inhibitory domain of PKG is released allowing binding of ATP in the catalytic domain and subsequent phosphorylation of target proteins.…”

Section: Interaction Of Pkg and The Wnt Signaling Cascadementioning

confidence: 99%

The interaction between the Wnt/β-catenin signaling cascade and PKG activation in cancer

Lee

Piazza

2017

J Biomed Res

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The activation of the Wnt/β-catenin signaling cascade has been well studied and documented in colorectal cancer (CRC). The long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) has been shown to reduce the incidence and risk of death from CRC in numerous epidemiological studies. The NSAID sulindac has also been reported to cause regression of precancerous adenomas in individuals with familial adenomatous polyposis who are at high risk of developing CRC. The mechanism responsible for cancer chemopreventive activity of NSAIDs is not well understood but may be unrelated to their cyclooxygenase inhibitory activity. Emerging evidence suggests that sulindac inhibits the growth of colon tumor cells by suppressing the activity of certain phosphodiesterase isozymes to activate cGMP-dependent protein kinase, PKG, through the elevation of the second messenger cyclic guanosine monophosphote, cGMP. PKG activation has been shown to inhibit the nuclear translocation of β-catenin, reduce β-catenin mRNA and protein levels, and suppress the transcriptional activity of β-catenin. This review describes the relationship between the Wnt/β-catenin signaling cascade and the activation of PKG through PDE inhibition and elevation of intracellular cGMP levels.

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Section: Interaction Of Pkg and The Wnt Signaling Cascadementioning

confidence: 99%

The interaction between the Wnt/β-catenin signaling cascade and PKG activation in cancer

Lee

Piazza

2017

J Biomed Res

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“…In the intestine, GUCY2C-activated cGMP signaling regulates ion channels including the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel and CNG cation channels [4]. GUCY2C also inhibits sodium absorption from the intestinal lumen by sodium-hydrogen exchangers in brush border membranes [2, 4, 49]. In the brain, cGMP-dependent activation of CNG channels regulates neurotransmitter release and potentiates synaptic transmission through Ca 2+ influx [50, 51].…”

Section: Potential Molecular Mechanisms Underlying Gucy2c-mediated Samentioning

confidence: 99%

“…By decreasing AKT activation, GUCY2C signaling suppresses cell proliferation. Tellingly, the GUCY2C hormone guanylin is the most commonly lost gene product in sporadic colorectal cancer in mice and humans [49, 67]. GUCY2C silencing produces epithelial dysfunction, which is characterized by defective differentiation, an accelerated cell cycle, hyperproliferation, increased DNA damage, reprogramming of cell metabolism, and increased susceptibility to tumorigenesis induced by carcinogens or inherited germline mutations, resulting in increased intestinal tumorigenesis [5, 67].…”

Section: Obesity and Colorectal Cancermentioning

confidence: 99%

GUCY2C: at the intersection of obesity and cancer

Kim

Lin

2013

Trends in Endocrinology & Metabolism

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Guanylyl cyclase C (GUCY2C) has canonical centrality in defense of key intestinal homeostatic mechanisms, encompassing fluid and electrolyte balance, epithelial dynamics, antitumorigenesis, and intestinal barrier function. Recent discoveries expand the homeostatic role of GUCY2C to reveal a novel gut-brain endocrine axis regulating appetite, anchored by hypothalamic GUCY2C which is responsive to intestine-derived uroguanylin. Thus, GUCY2C may represent a new target for anti-obesity pharmacotherapy. Moreover, the coincident regulation of energy balance and tumor suppression by a single hormone receptor system suggests that the GUCY2C axis might contribute to the established relationship between obesity and colorectal cancer. This confluence suggests that hormone supplementation to reconstitute GUCY2C signaling may be an elegant strategy to reverse both pathophysiologic processes.

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“…Beyond systemic volume homeostasis, GC-C/cGMP signal transduction mechanisms activated by GN and UGN regulate the formation of epithelial cells in the intestinal mucosa [98, 103]. Pitari et al [104] have shown that GN and UGN can regulate the balance between epithelial proliferation and differentiation, and can regulate cell cycle progression in human colon carcinoma cell lines.…”

Section: Non-classical Roles Of Guanylin Peptidesmentioning

confidence: 99%

“…GN and UGN exert a cytostatic effect on human colon carcinoma cells [109] and pancreatic cancer cells [110], and inhibit formation of cancerous intestinal polyps in mice [109]. Collectively, these data suggest that the UGN/GC-C/cGMP axis may have generalized antiproliferative properties in various organ systems [98, 103, 110, 111]. …”

Section: Non-classical Roles Of Guanylin Peptidesmentioning

confidence: 99%

Pendrin, a Novel Transcriptional Target of the Uroguanylin System

Rozenfeld

Tal

Kladnitsky

et al. 2013

Cell Physiol Biochem

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Guanylin (GN) and uroguanylin (UGN) are low-molecular-weight peptide hormones produced mainly in the intestinal mucosa in response to oral salt load. GN and UGN (guanylin peptides) induce secretion of electrolytes and water in both intestine and kidney. Thought to act as “intestinal natriuretic factors”, GN and UGN modulate renal salt secretion by both endocrine mechanisms (linking the digestive system and kidney) and paracrine/autocrine (intrarenal) mechanisms. The cellular function of GN and UGN in intestine and proximal tubule is mediated by guanylyl cyclase C (GC-C)-, cGMP-, and G protein-dependent pathways, whereas, in principal cells of the cortical collecting duct (CCD), these peptide hormones act via GC-C-independent signaling through phospholipase A₂ (PLA₂). The Cl^-/HCO^-₃ exchanger pendrin (SLC26A4), encoded by the PDS gene, is expressed in non-α intercalated cells of the CCD. Pendrin is essential for CCD bicarbonate secretion and is also involved in NaCl balance and blood pressure regulation. Our recent studies have provided evidence that pendrin-mediated anion exchange in the CCD is regulated at the transcriptional level by UGN. UGN exerts an inhibitory effect on the pendrin gene promoter likely via heat shock factor 1 (HSF1) action at a defined heat shock element (HSE) site. Recent studies have unraveled novel roles for guanylin peptides in several organ systems including involvement in appetite regulation, olfactory function, cell proliferation and differentiation, inflammation, and reproductive function. Both the guanylin system and pendrin have also been implicated in airway function. Future molecular research into the receptors and signal transduction pathways involved in the action of guanylin peptides and the pendrin anion exchanger in the kidney and other organs, and into the links between them, may facilitate discovery of new therapies for hypertension, heart failure, hepatic failure and other fluid retention syndromes, as well as for diverse diseases such as obesity, asthma, and cancer.

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The uroguanylin system and human disease

Cited by 14 publications

References 81 publications

The interaction between the Wnt/β-catenin signaling cascade and PKG activation in cancer

The interaction between the Wnt/β-catenin signaling cascade and PKG activation in cancer

GUCY2C: at the intersection of obesity and cancer

Pendrin, a Novel Transcriptional Target of the Uroguanylin System

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