ZIP7-Mediated Intracellular Zinc Transport Contributes to Aberrant Growth Factor Signaling in Antihormone-Resistant Breast Cancer Cells

Taylor, KM; Vichova, Petra; Jordan, Nicola; Hiscox, Stephen Edward; Hendley, Rhiannon; Nicholson, Robert Ian

doi:10.1210/en.2008-0351

Cited by 207 publications

(252 citation statements)

References 38 publications

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“…Passive diffusion of zinc across cell membranes is not possible 26 . Bozym et al 27 investigated the effect of cell culture medium on the intracellular Zn (II) concentration and found that both the type of cell and the medium influence the intracellular free Zn (II) level during exposure to a certain concentration of Zn (II) and that the toxicity of supplemented Zn (II) must be carefully investigated.…”

Section: Discussionmentioning

confidence: 99%

Effects of non-toxic zinc exposure on human epidermal keratinocytes

et al. 2015

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Zinc is an essential microelement; its importance to skin is shown by severe skin symptoms in hereditary or acquired zinc deficiency, by the improvement of several skin conditions using systemic or topical zinc preparations and by the induced intracellular zinc release upon UVB exposure, which is the main harmful environmental factor to skin. Understanding the molecular background of the role of zinc in skin may help to gain insight into the pathology of skin disorders and to provide evidence for the therapeutic usefulness of zinc supplementation.Herein, we studied the effect of zinc chloride (ZnCl 2 ) exposure on the function of HaCaT keratinocytes, and we found that a non-toxic elevation in the concentration of extracellular zinc (100 µM) facilitated cell proliferation and induced significant alterations in the mRNA expression of NOTCH1, IL8, and cyclooxygenase-2. In addition, we detected increased heme oxygenase-1 (HMOX1) expression and non-toxic generation of superoxide in the first 4 h.Regarding the effect on UVB-induced toxicity, although the level of cyclobutane pyrimidine dimers in keratinocytes pre-treated with zinc for 24 h was reduced 3 h after UVB irradiation, we found significantly enhanced superoxide generation 10 h after UVB exposure in the zinc pre-exposed cells. The overall survival was unaffected; however, there was a decrease in the percentage of early apoptotic cells and an increase in the percentage of late apoptotic plus necrotic cells.Our results suggest that exposure of human keratinocytes to non-toxic concentrations of ZnCl 2 impacts gene expression, cell proliferation and the response to environmental stress in skin. It would be important to further examine the role of zinc in skin and to further clarify if this issue can affect our thinking about the pathogenesis of skin diseases.

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Section: Discussionmentioning

confidence: 99%

Effects of non-toxic zinc exposure on human epidermal keratinocytes

et al. 2015

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“…For Peer Review Only Diabetes other systems (17). Additionally, it has been hypothesized that protein kinase-2 (CK2) triggers cytosolic Zn…”

Section: Page 3 Of 73mentioning

confidence: 99%

Hyperglycemia-Induced Changes in ZIP7 and ZnT7 Expression Cause Zn2+ Release From the Sarco(endo)plasmic Reticulum and Mediate ER Stress in the Heart

et al. 2017

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Changes in cellular free Zn 2+ concentration, including those in the sarco(endo)plasmic reticulum [S(E)R], are primarily coordinated by Zn 2+-transporters whose identity and role in the heart is not well established. Here, we hypothesized that ZIP7 and ZnT7 transport Zn 2+ in opposing directions across the S(E)R membrane in cardiomyocytes and that changes in their activity may play an important role in the development of ER-stress during hyperglycemia.The subcellular S(E)R-localization of ZIP7 and ZnT7 was determined in cardiomyocytes and in isolated S(E)R-preparations. Markedly increased mRNA and protein levels of ZIP7 were observed in ventricular cardiomyocytes from diabetic rats or high glucose-treated H9c2 cells whilst ZnT7 expression was low. Additionally, we observed increased ZIP7-phosphorylation in response to high glucose in vivo and in vitro. Using recombinant targeted FRET-based sensors, we showed that hyperglycemia induced a marked redistribution of cellular free Zn 2+ , increasing cytosolic free Zn 2+ and lowering free Zn 2+ in the S(E)R. These changes involve alterations in ZIP7-phosphorylation and were suppressed by siRNA-mediated silencing of CK2α. Opposing changes in the expression of ZIP7 and ZnT7 were also observed in hyperglycemia. We conclude that sub-cellular free Zn 2+ re-distribution in the hyperglycemic heart, resulting from altered ZIP7 and ZnT7 activity, contributes to cardiac dysfunction in diabetes.

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“…Zinc also inhibits protein tyrosine phosphatases, preserving signaling by the insulin and EGF receptors [28][29][30]. The IL-2R itself, as well as JAK1 and 3 and STAT5, are activated by tyrosine phosphorylation [10].…”

Section: Impact Of Zinc Signals On Erk and Stat5 Signalingmentioning

confidence: 99%

Zinc signals promote IL‐2‐dependent proliferation of T cells

et al. 2010

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Zinc signals, i.e. a change of the intracellular concentration of free zinc ions in response to receptor stimulation, are involved in signal transduction in several immune cells. Here, the role of zinc signals in T-cell activation by IL-2 was investigated in the murine cytotoxic T-cell line CTLL-2 and in primary human T cells. Measurements with the fluorescent dyes FluoZin-3 and Zinquin showed that zinc is released from lysosomes into the cytosol in response to stimulation of the IL-2-receptor. Activation of the ERK-pathway was blocked by chelation of free zinc with N,N,N 0 ,N 0 -tetrakis-2(pyridyl-methyl)ethylenediamine, whereas zinc was not required for STAT5 phosphorylation. In addition, the key signaling molecules MEK and ERK were activated in response to elevated free intracellular zinc, induced by incubation with zinc and the ionophore pyrithione. Downstream of ERK activation, ERK-specific gene expression of c-fos and IL-2-induced proliferation was found to depend on zinc. Further experiments indicated that inhibition of MEK and ERK-dephosphorylating protein phosphatases is the molecular mechanism for the influence of zinc on this pathway. In conclusion, an increase of cytoplasmic free zinc is required for IL-2-induced ERK signaling and proliferation of T cells. Key words: IL-2 . T cells . Zinc Supporting Information available online IntroductionZinc signals have been observed in different cell types of the immune system, including monocytes, dendritic cells, and mast cells [1]. T-cell function is particularly susceptible to zinc deprivation, and zinc signals were suggested to activate protein kinase C in T cells [1,2]. Furthermore, zinc is involved in the activation of the Src-family kinase Lck by the TCR. Here, zinc ions are required for interactions at two protein/protein interface sites. First, they stabilize the interaction between Lck and CD4 or CD8, recruiting the kinase to the TCR signaling complex [3]. Second, zinc ions stabilize homodimerization of Lck, which promotes activating transphosphorylation between two Lck molecules [4]. Cellular zinc homeostasis is mediated by ten members of the ZnT family and 14 members of the Zrt-, Irt-like protein (ZIP) family of zinc transporters [5]. Intracellular localization for most of these transporters remains to be determined. So far, no nuclear zinc transporters were identified, even though there is evidence that nuclear and cytoplasmic zinc are differentially regulated [6]. In general, ZIP transport zinc into the cytoplasm, whereas ZnT transport zinc out of the cell or into cellular compartments, SHORT COMMUNICATION 1496including different vesicular structures [7]. Importantly, zinc accumulates in a lysosomal compartment of T cells, from which it is released by ZIP8 in response to TCR-mediated activation by antibodies against CD2, CD3, and CD28 [8].Previously, zinc was also shown to be required for T-cell activation by IL-2, a growth-factor that stimulates proliferation of T cells [9]. These data point to IL-2 signaling as another target for zinc in T cell...

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ZIP7-Mediated Intracellular Zinc Transport Contributes to Aberrant Growth Factor Signaling in Antihormone-Resistant Breast Cancer Cells

Cited by 207 publications

References 38 publications

Effects of non-toxic zinc exposure on human epidermal keratinocytes

Effects of non-toxic zinc exposure on human epidermal keratinocytes

Hyperglycemia-Induced Changes in ZIP7 and ZnT7 Expression Cause Zn2+ Release From the Sarco(endo)plasmic Reticulum and Mediate ER Stress in the Heart

Zinc signals promote IL‐2‐dependent proliferation of T cells

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