Enhanced ZnR/GPR39 Activity in Breast Cancer, an Alternative Trigger of Signaling Leading to Cell Growth

Ventura-Bixenshpaner, Hila; Asraf, Hila; Chakraborty, Moumita; Elkabets, Moshe; Sekler, Israel; Taylor, KM; Hershfinkel, Michal

doi:10.1038/s41598-018-26459-5

Cited by 18 publications

(22 citation statements)

References 76 publications

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“…Activation of ZnR/GPR39, by Zn 2+ , triggered upregulation of MAPK and AKT/PI3K signaling pathways in ZnR/GPR39 expressing breast cancer cells. In agreement, unbiased screens identified a correlation between upregulation of GPR39 and the aggressiveness of breast cancer cell lines and tissues [7,8]. Changes in Zn 2+ levels and in the expression of Zn 2+ transporters are also monitored in breast cancer tissues [9][10][11][12], this dys-homeostasis may trigger release of Zn 2+ and subsequent activation of ZnR/GPR39.…”

Section: Introductionsupporting

confidence: 53%

“…1A). The response was triggered by a brief exposure to 200µM Zn 2+ , which activates ZnR/GPR39 in breast cancers cells but does not induce intracellular Zn 2+ rise [7].…”

Section: Resultsmentioning

confidence: 99%

“…Mechanisms underlying this resistance involve loss of the ER and activation of downstream signaling pathways, such as the mitogen activated kinase (MAPK) and phosphatidylinositol 3-kinase (AKT/PI3K), independent of estrogen [5,6]. Notable, expression of a Zn 2+ -sensing G-protein coupled receptor, ZnR/GPR39, is increased in higher stage ER-negative breast cancer tissue and in ERnegative breast cancer cell lines, compared to ER expressing cells [7]. Activation of ZnR/GPR39, by Zn 2+ , triggered upregulation of MAPK and AKT/PI3K signaling pathways in ZnR/GPR39 expressing breast cancer cells.…”

Section: Introductionmentioning

confidence: 99%

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ZnR/GPR39 upregulation of K+/Cl−-cotransporter 3 in tamoxifen resistant breast cancer cells

et al. 2019

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Section: Introductionsupporting

confidence: 53%

“…1A). The response was triggered by a brief exposure to 200µM Zn 2+ , which activates ZnR/GPR39 in breast cancers cells but does not induce intracellular Zn 2+ rise [7].…”

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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ZnR/GPR39 upregulation of K+/Cl−-cotransporter 3 in tamoxifen resistant breast cancer cells

et al. 2019

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“…Secondary anti-mouse and anti-rabbit antibodies (Jackson Immunoesearch, West Grove, PA, USA) were used at dilutions of 1:20,000 and 1:40,000, respectively. Densitometry analysis of expression level was performed using EZQuant-Gel software (EZQuant, Hertzliya Pituach, Israel) as previously described [55].…”

Section: Immunoblot Analysismentioning

confidence: 99%

Elucidating the H+ Coupled Zn2+ Transport Mechanism of ZIP4; Implications in Acrodermatitis Enteropathica

Hoch¹,

Levy²,

Hershfinkel³

et al. 2020

IJMS

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Cellular Zn2+ homeostasis is tightly regulated and primarily mediated by designated Zn2+ transport proteins, namely zinc transporters (ZnTs; SLC30) that shuttle Zn2+ efflux, and ZRT-IRT-like proteins (ZIPs; SLC39) that mediate Zn2+ influx. While the functional determinants of ZnT-mediated Zn2+ efflux are elucidated, those of ZIP transporters are lesser understood. Previous work has suggested three distinct molecular mechanisms: (I) HCO3− or (II) H+ coupled Zn2+ transport, or (III) a pH regulated electrodiffusional mode of transport. Here, using live-cell fluorescent imaging of Zn2+ and H+, in cells expressing ZIP4, we set out to interrogate its function. Intracellular pH changes or the presence of HCO3− failed to induce Zn2+ influx. In contrast, extracellular acidification stimulated ZIP4 dependent Zn2+ uptake. Furthermore, Zn2+ uptake was coupled to enhanced H+ influx in cells expressing ZIP4, thus indicating that ZIP4 is not acting as a pH regulated channel but rather as an H+ powered Zn2+ co-transporter. We further illustrate how this functional mechanism is affected by genetic variants in SLC39A4 that in turn lead to Acrodermatitis enteropathica, a rare condition of Zn2+ deficiency.

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“…NCOA1 was found to promote angiogenesis in breast cancers [33]. SLC39A7 is a potential oncogene in colorectal cancer [34]. IDH3B is upregulated in breast cancer and is significantly involved in energy metabolism in tumor progression [35,36].…”

Section: Quantitative and Qualitative Assessment Of Quadmutnetex Resultsmentioning

confidence: 99%

QuaDMutNetEx: a method for detecting cancer driver genes with low mutation frequency

2020

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Background: Cancer is caused by genetic mutations, but not all somatic mutations in human DNA drive the emergence or growth of cancers. While many frequently-mutated cancer driver genes have already been identified and are being utilized for diagnostic, prognostic, or therapeutic purposes, identifying driver genes that harbor mutations occurring with low frequency in human cancers is an ongoing endeavor. Typically, mutations that do not confer growth advantage to tumors-passenger mutations-dominate the mutation landscape of tumor cell genome, making identification of low-frequency driver mutations a challenge. The leading approach for discovering new putative driver genes involves analyzing patterns of mutations in large cohorts of patients and using statistical methods to discriminate driver from passenger mutations. Results: We propose a novel cancer driver gene detection method, QuaDMutNetEx. QuaDMutNetEx discovers cancer drivers with low mutation frequency by giving preference to genes encoding proteins that are connected in human protein-protein interaction networks, and that at the same time show low deviation from the mutual exclusivity pattern that characterizes driver mutations occurring in the same pathway or functional gene group across a cohort of cancer samples. Conclusions: Evaluation of QuaDMutNetEx on four different tumor sample datasets show that the proposed method finds biologically-connected sets of low-frequency driver genes, including many genes that are not found if the network connectivity information is not considered. Improved quality and interpretability of the discovered putative driver gene sets compared to existing methods shows that QuaDMutNetEx is a valuable new tool for detecting driver genes. QuaDMutNetEx is available for download from https://github.com/bokhariy/QuaDMutNetEx under the GNU GPLv3 license.

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Enhanced ZnR/GPR39 Activity in Breast Cancer, an Alternative Trigger of Signaling Leading to Cell Growth

Cited by 18 publications

References 76 publications

ZnR/GPR39 upregulation of K+/Cl−-cotransporter 3 in tamoxifen resistant breast cancer cells

ZnR/GPR39 upregulation of K+/Cl−-cotransporter 3 in tamoxifen resistant breast cancer cells

Elucidating the H+ Coupled Zn2+ Transport Mechanism of ZIP4; Implications in Acrodermatitis Enteropathica

QuaDMutNetEx: a method for detecting cancer driver genes with low mutation frequency

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