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Induction of human metallothionein 1G promoter by VEGF and heavy metals: differential involvement of E2F and metal transcription factors

Oncogene volume 24, pages 2204–2217 (2005)Cite this article

Abstract

The E2F transcription factors induce the expression of many genes in response to specific extracellular stimuli. Here, we show that human metallothionein 1G (hMT1G) promoter is upregulated by E2F1 upon VEGF stimulation of human aortic endothelial cells. Analysis of the hMT1G promoter showed the presence of many potential E2F-binding sites flanked by potential SP1 sites and metal response elements (MREs). hMT1G promoter could be induced by E2F1 in transient transfections; further, deletion analysis suggested that the region spanning the E2F-binding sites was necessary for VEGF-mediated induction. E2Fs 1–5 could bind to the hMT1G promoter in a chromatin immunoprecipitation assay. VEGF stimulation led to an increased binding of E2Fs 1–3 to the endogenous hMT1G promoter; at the same time, the binding of Rb, p107 and p130 to the promoter was abolished. VEGF stimulation also led to the increased acetylation E2F1 as well as the histones in the hMT1G promoter region. Stimulation with metals or VEGF led to dissociation of histone deacetylase 1 (HDAC1) from the promoter, leading to acetylation of histones. Induction of the hMT1G promoter upon exposure to heavy metals such as Zn and Cd is mediated by the MRE. Interestingly, mutation of MRE affected the metal response, but not the VEGF response of the hMT1G promoter. In contrast, deletion of the E2F-binding sites did not affect the metal response. Based on these findings, we conclude that induction of the hMT1G promoter by VEGF and heavy metals occurs through the utilization of different transcription factors.

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Acknowledgements

We thank Dr Ed Seto for helpful discussions as well as for providing the MTF1 expression vector. Assistance from Core Facilities for microarray analysis, molecular biology and analytical microscopy at the Moffitt Cancer Center is gratefully acknowledged. This study was supported by the Grant CA63136 from the NCI to SPC.

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  1. Department of Interdisciplinary Oncology, H Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL, 33612, USA

    Bharat Joshi, Dalia Ordonez-Ercan, Piyali Dasgupta & Srikumar Chellappan

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  1. Bharat Joshi
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Correspondence to Srikumar Chellappan.

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Joshi, B., Ordonez-Ercan, D., Dasgupta, P. et al. Induction of human metallothionein 1G promoter by VEGF and heavy metals: differential involvement of E2F and metal transcription factors. Oncogene 24, 2204–2217 (2005). https://doi.org/10.1038/sj.onc.1208206

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