Metallothionein transfers zinc to mitochondrial aconitase through a direct interaction in mouse hearts

Feng, Wenke; Cai, Jian; Pierce, William M.; Franklin, Renty B.; Maret, Wolfgang; Benz, Frederick W.; Kang, Y. James

doi:10.1016/j.bbrc.2005.04.170

Cited by 99 publications

(61 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Immunoprecipitation was performed using anti-HIF-1␣ or anti-p300 (BD Biosciences) antibodies as described previously (Feng et al, 2005). The immunoprecipitates were subjected to Western blotting analysis as described above.…”

Section: Methodsmentioning

confidence: 99%

Copper Regulation of Hypoxia-Inducible Factor-1 Activity

et al. 2008

Self Cite

View full text Add to dashboard Cite

Copper deficiency suppresses and copper addition enhances the expression of vascular endothelial growth factor (VEGF), which is primarily controlled by hypoxia‐inducible factor 1 (HIF‐1) transcription factor. The regulatory subunit of HIF‐1α senses oxygen availability and is also affected by various transition metals. The purpose of this study was to determine whether or not copper is required for activation of HIF‐1. Copper depletion by copper chelator tetraethylenepentamine (TEPA) decreased the hypoxia‐induced transactivity of HIF‐1, assessed by hypoxia responsive element‐dependent luciferase reporter assay, but not HIF‐1α protein level in HepG2 cells. Further examination showed that one of the copper chaperonesfor Cu,Zn‐SOD (CCS) is also involved in the HIF‐1 activation. CCS depletion by siRNA attenuated HIF‐1 transactivity along with decreases in VEGF expression under both normoxic and hypoxic conditions. HIF‐1α could be co‐immunoprecipitated by anti‐CCS antibody in the nuclear extract of HepG2 cells under hypoxic conditions, implying a direct interaction between HIF‐1α and CCS. These results suggested that copper is required for HIF‐1α transcriptional activation and the copper chaperone CCS is critically involved. Supported by NIH grants HL59225 and HL63760 and Kentucky Science and Engineering Foundation Grant 008‐888.

show abstract

Section: Methodsmentioning

confidence: 99%

Copper Regulation of Hypoxia-Inducible Factor-1 Activity

et al. 2008

Self Cite

View full text Add to dashboard Cite

show abstract

“…On the other hand, given their capacity to influence zinc metabolism and this metal's availability to many zinc-dependent proteins and transcription factors, other studies have associated them with chemosensitivity (8,9). Indeed, MTs either donate or take away zinc ions from several zinc-dependent proteins, including p53 (10,11), thereby regulating their function. We and others have previously demonstrated that these proteins are progressively silenced during colorectal cancer progression, and that this is associated to poorer patient survival.…”

Section: Introductionmentioning

confidence: 99%

Metallothionein 1G and Zinc Sensitize Human Colorectal Cancer Cells to Chemotherapy

Arriaga

Greco

Mordoh

et al. 2014

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Metallothioneins (MT) are a family of low molecular weight proteins that are silenced during colorectal cancer progression, mainly through epigenetic mechanisms, and this loss is associated with poor survival. In this article, we show that overexpression of the MT1G isoform sensitizes colorectal cell lines to the chemotherapeutic agents oxaliplatin (OXA) and 5-fluorouracil (5-FU), in part through enhancing p53 and repressing NF-kB activity. Despite being silenced, MTs can be reinduced by histone deacetylase inhibitors such as trichostatin A and sodium butyrate. In fact, this induction contributes to the cytotoxicity of these agents, given that silencing of MTs by siRNAs reduces their growth-inhibitory activities. Zinc ions also potently enhance MT expression and are cytotoxic to cancer cells. We show for the first time that OXA and 5-FU induce higher levels of intracellular labile zinc, as measured using the fluorescent probe FLUOZIN-3, and that such zinc contributes to the activation of p53 and repression of NF-kB. Addition of zinc enhanced growth inhibition by OXA and 5-FU, and was also capable of resensitizing 5-FU-resistant cell lines to levels comparable with sensitive cell lines. This effect was MT independent because silencing MTs did not affect zinc cytotoxicity. In conclusion, we show that MT induction and zinc administration are novel strategies to sensitize colorectal cancer cells to presently utilized chemotherapeutic agents. Mol Cancer Ther; 13(5); 1369-81. Ó2014 AACR.

show abstract

“…Protein preparations from heart tissues were obtained as described previously 25,26 with modifications. Briefly, after …”

Section: Western Blot Analysismentioning

confidence: 99%

Cardiac-Specific Overexpression of HIF-1α Prevents Deterioration of Glycolytic Pathway and Cardiac Remodeling in Streptozotocin-Induced Diabetic Mice

Xue¹,

Cai²,

Tan³

et al. 2010

The American Journal of Pathology

Self Cite

View full text Add to dashboard Cite

Defective glycolysis and angiogenesis in the heart of diabetic patients and in experimental diabetic animal models have been reported. The aim of this study was to determine whether overexpression of hypoxia-inducible factor (HIF)-1␣ protects from myocardial injury in diabetic mice by increasing myocardial glycolysis and angiogenesis. Cardiac-specific HIF-1␣-overexpressing transgenic and age-matched wild-type control mice were treated with streptozotocin to induce diabetes. Changes in glucose transporters, glycolytic enzymes, angiogenic factors and cardiac morphology were examined in the hearts by real-time RT-PCR, Western blotting, enzymatic assay, and histological assays. HIF-1␣ overexpression elevated hexokinase II (HK-II) protein level and total HK activity in nondiabetic heart and prevented the decreases in HK-II mRNA, protein, and total HK activity in diabetic heart. In addition, the reduction of glucose transporter I, but not glucose transporter 4, was restored in HIF transgenic mouse heart along with a recovery of myocardium ATP production. HIF-1␣ overexpression also normalized diabetes-reduced vascular endothelial growth factor concentration along with a sustained myocardial capillary density and an inhibition of cardiomyocyte hypertrophy and cardiac fibrosis. Therefore, elevation of HIF-1␣ provides a cardiac protection from diabetic-induced impairment in glucose metabolism and angiogenesis via up-regulation of HIF-1 target genes.

show abstract

Metallothionein transfers zinc to mitochondrial aconitase through a direct interaction in mouse hearts

Cited by 99 publications

References 33 publications

Copper Regulation of Hypoxia-Inducible Factor-1 Activity

Copper Regulation of Hypoxia-Inducible Factor-1 Activity

Metallothionein 1G and Zinc Sensitize Human Colorectal Cancer Cells to Chemotherapy

Cardiac-Specific Overexpression of HIF-1α Prevents Deterioration of Glycolytic Pathway and Cardiac Remodeling in Streptozotocin-Induced Diabetic Mice

Contact Info

Product

Resources

About