Stimulation of HERG Channel Activity by β-catenin

Muñoz, Carlos; Saxena, Ambrish; Pakladok, Tatsiana; Bogatikov, Evgenii; Wilmes, Jan; Seebohm, Guiscard; Föller, Michael; Läng, Florian

doi:10.1371/journal.pone.0043353

Cited by 4 publications

(2 citation statements)

References 48 publications

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“…It is known that the main function of Apc is to degrade cytosolic levels of b-catenin, whose dysregulation is considered a major cause of tumor development. As previous studies from Carlos Munoz's laboratory showed that b-catenin increased the hERG1 protein levels within the oocyte cell membrane [42], the increased hERG1 channel activity detected in the polyps of Apc min/+ mice could be attributed to the overexpression of b-catenin, widely described in this animal model [43]. It is worth noting that, at difference from what happens in the small intestine, the loss of function of Apc is not sufficient per se to trigger the development of tumors in the colon, where adjunctive genetic events are required for the transition from microadenomas to macroscopic tumors to be accomplished [44].…”

Section: Discussionmentioning

confidence: 73%

Characterization of hERG1 channel role in mouse colorectal carcinogenesis

et al. 2013

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The human ether-à-go-go-related gene (hERG)1 K+ channel is upregulated in human colorectal cancer cells and primary samples. In this study, we examined the role of hERG1 in colorectal carcinogenesis using two mouse models: adenomatous polyposis coli (Apcmin/+) and azoxymethane (AOM)-treated mice. Colonic polyps of Apcmin/+ mice overexpressed mERG1 and their formation was reverted by the hERG1 blocker E4031. AOM was applied to either hERG1-transgenic (TG) mice, which overexpress hERG1 in the mucosa of the large intestine, or wild-type mice. A significant increase of both mucin-depleted foci and polyps in the colon of hERG1-TG mice was detected. Both the intestine of TG mice and colonic polyps of Apcmin/+ showed an upregulation of phospho-Protein Kinase B (pAkt)/vascular endothelial growth factor (VEGF-A) and an increased angiogenesis, which were reverted by treatment with E4031. On the whole, this article assigns a relevant role to hERG1 in the process of in vivo colorectal carcinogenesis.

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Section: Discussionmentioning

confidence: 73%

Characterization of hERG1 channel role in mouse colorectal carcinogenesis

et al. 2013

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“…In support of this, β-catenin is found to co-localize with insulin granules at cell junctions in MIN6 pseudoislets [58]. Another explanation would be a regulation of ion fluxes, since there is a significant body of evidence that β-catenin can regulate the location and/or function of ion transporters at the plasma membrane in β-cells [59][60][61][62][63]. The resulting changes in ion currents could affect insulin granule release.…”

Section: Discussionmentioning

confidence: 90%

Identification of a pathway by which glucose regulates β-catenin signalling via the cAMP/protein kinase A pathway in β-cell models

Cognard

Dargaville

Hay

et al. 2013

Biochemical Journal

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Pancreatic β-cells are highly responsive to changes in glucose, but the mechanisms involved are only partially understood. There is increasing evidence that the β-catenin signalling pathway plays an important role in regulating β-cell function, but the mechanisms regulating β-catenin signalling in these cells is not well understood. In the present study we show that β-catenin levels and downstream signalling are regulated by changes in glucose levels in INS-1E and β-TC6-F7 β-cell models. We found a glucose-dependent increase in levels of β-catenin in the cytoplasm and nucleus of INS-1E cells. Expression of cyclin D1 also increased with glucose and required the presence of β-catenin. This was associated with an increase in phosphorylation of β-catenin on Ser552, which is known to stabilize the molecule and increase its transcriptional activity. In a search for possible signalling intermediates we found forskolin and cell-permeable cAMP analogues recapitulated the glucose effects, suggesting a role for cAMP and PKA (cAMP-dependent protein kinase/protein kinase A) downstream of glucose. Furthermore, glucose caused sustained increases in cAMP. Two different inhibitors of adenylate cyclase and PKA signalling blocked the effects of glucose, whereas siRNA (small interfering RNA) knockdown of PKA blocked the effects of glucose on β-catenin signalling. Finally, reducing β-catenin levels with either siRNA or pyrvinium impaired glucose- and KCl-stimulated insulin secretion. Taken together the results of the present study define a pathway by which changes in glucose levels can regulate β-catenin using a mechanism which involves cAMP production and the activation of PKA. This identifies a pathway that may be important in glucose-dependent regulation of gene expression and insulin secretion in β-cells.

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HERG channel and cancer: A mechanistic review of carcinogenic processes and therapeutic potential

Moutaoufik

Islam

et al. 2020

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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Stimulation of HERG Channel Activity by β-catenin

Cited by 4 publications

References 48 publications

Characterization of hERG1 channel role in mouse colorectal carcinogenesis

Characterization of hERG1 channel role in mouse colorectal carcinogenesis

Identification of a pathway by which glucose regulates β-catenin signalling via the cAMP/protein kinase A pathway in β-cell models

HERG channel and cancer: A mechanistic review of carcinogenic processes and therapeutic potential

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