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Tumor Biology

Abstract LB-377: Regulation of expression of choline kinase by a conserved HIF1 binding hypoxia-responsive element

Aditya Bansal, Robert A. Harris and Timothy R. DeGrado
Aditya Bansal
1Brigham And Women's Hospital. Harvard Medical School, Boston, MA
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Robert A. Harris
2Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indiana, IN.
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Timothy R. DeGrado
1Brigham And Women's Hospital. Harvard Medical School, Boston, MA
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DOI: 10.1158/1538-7445.AM10-LB-377 Published April 2010
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Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC

Abstract

Hypoxic microenvironment and overexpression of choline kinase alpha (ChKa) have been associated with tumor malignancy, but the regulation of ChKa expression in hypoxic conditions is poorly understood. In this study, the effects of chronic hypoxia on choline metabolism and ChKa expression were examined in prostate cancer cell line, PC-3. Chronic hypoxia (1% O2, 24h) decreased proliferation rate and intracellular levels of phosphocholine, while intracellular levels of free choline were increased. Choline tracer uptake and washout studies confirmed the decreased rate of choline phosphorylation in hypoxic cells. Overexpression of HIF1a or DMOG exposure in normoxic PC-3 cells decreased both choline uptake and choline kinase activity. RT-PCR analysis showed decreased transcription of ChKa gene in hypoxic PC-3 correlating with decreased enzymatic activity of choline kinase in hypoxic cell extracts. Alignment of nucleotide sequence of the putative promoter region of ChKa from rat, mouse, chimpanzee and human revealed a highly conserved hypoxia responsive element upstream to transcription start site of ChKa. Electrophoretic mobility shift competition/supershift assay and chromatin immunoprecipitation-quantitative PCR assay confirmed binding of native HIF-1α protein to the conserved HRE. To understand the transcription control of ChKa under hypoxia, a putative promoter of ChKa was isolated from PC-3 genomic DNA and cloned into a luciferase (Luc) based reporter vector system. In PC-3, hypoxia decreased the expression of Luc under the control of the ChKa promoter. Mutation of the conserved HRE and subsequent Luc reporter assays demonstrated that this HRE is involved in hypoxia/HIF1α mediated regulation of ChKa. The results suggest that the decreased choline phosphorylation in PC-3 cells in response to hypoxia is mediated in part by the newly-identified conserved HIF1α binding HRE.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-377.

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Cancer Research: 70 (8 Supplement)
April 2010
Volume 70, Issue 8 Supplement
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Abstract LB-377: Regulation of expression of choline kinase by a conserved HIF1 binding hypoxia-responsive element
Aditya Bansal, Robert A. Harris and Timothy R. DeGrado
Cancer Res April 15 2010 (70) (8 Supplement) LB-377; DOI: 10.1158/1538-7445.AM10-LB-377

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Abstract LB-377: Regulation of expression of choline kinase by a conserved HIF1 binding hypoxia-responsive element
Aditya Bansal, Robert A. Harris and Timothy R. DeGrado
Cancer Res April 15 2010 (70) (8 Supplement) LB-377; DOI: 10.1158/1538-7445.AM10-LB-377
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Cancer Research Online ISSN: 1538-7445
Cancer Research Print ISSN: 0008-5472
Journal of Cancer Research ISSN: 0099-7013
American Journal of Cancer ISSN: 0099-7374

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