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Transcription Factor Sp1 Plays an Important Role in the Regulation of Copper Homeostasis in Mammalian Cells

Department of Molecular Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas (I.-S.S., H.H.W.C., I.A., A.H., Z.D.L., M.T.K.); Department of Pharmacology and Pharmacogenomics Research Center, Inje University College of Medicine, Busan, South Korea (I.-S.S.); Department of Radiation Oncology and Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan (H.H.W.C.); and Department of Metabolic and Endocrine Diseases, University Medical Center Utrecht, Utrecht, The Netherlands (L.W.J.K.)

Copper is an essential metal nutrient, yet copper overload is toxic. Here, we report that human copper transporter (hCtr) 1 plays an important role in the maintenance of copper homeostasis by demonstrating that expression of hCtr1 mRNA was up-regulated under copper-depleted conditions and down-regulated under copper-replete conditions. Overexpression of full-length hCtr1 by transfection with a recombinant hCtr1 cDNA clone reduced endogenous hCtr1 mRNA levels, whereas overexpression of N terminus-deleted hCtr1 did not change endogenous hCtr1 mRNA levels, suggesting that increased functional hCtr1 transporter, which leads to increased intracellular copper content, down-regulates the endogenous hCtr1 mRNA. A luciferase assay using reporter constructs containing the hCtr1 promoter sequences revealed that three Sp1 binding sites are involved in the basal and copper concentration-dependent regulation of hCtr1 expression. Modulation of Sp1 levels affected the expression of hCtr1. We further demonstrated that the zinc-finger domain of Sp1 functions as a sensor of copper that regulates hCtr1 up and down in response to copper concentration variations. Our results demonstrate that mammalian copper homeostasis is maintained at the hCtr1 mRNA level, which is regulated by the Sp1 transcription factor.

Address correspondence to: Dr. Macus Tien Kuo, Department of Molecular Pathology, Unit 951, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030. E-mail: tkuo{at}mdanderson.org

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				H. H. W. Chen, I.-S. Song, A. Hossain, M.-K. Choi, Y. Yamane, Z. D. Liang, J. Lu, L. Y.-H. Wu, Z. H. Siddik, L. W. J. Klomp, et al. Elevated Glutathione Levels Confer Cellular Sensitization to Cisplatin Toxicity by Up-Regulation of Copper Transporter hCtr1 Mol. Pharmacol., September 1, 2008; 74(3): 697 - 704. [Abstract] [Full Text] [PDF]