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J. Biol. Chem., Vol. 284, Issue 2, 1291-1301, January 9, 2009

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Regulation of Prion Gene Expression by Transcription Factors SP1 and Metal Transcription Factor-1^*

Shayne A. Bellingham^¶||1, Louise A. Coleman^¶, Colin L. Masters^||, James Camakaris, and Andrew F. Hill^¶||2

From the Departments of Biochemistry & Molecular Biology and Genetics, the ^¶Bio21 Molecular Science and Biotechnology Institute, and the ^||Mental Health Research Institute, The University of Melbourne, Victoria 3010, Australia

Prion diseases are associated with the conformational conversion of the host-encoded cellular prion protein into an abnormal pathogenic isoform. Reduction in prion protein levels has potential as a therapeutic approach in treating these diseases. Key targets for this goal are factors that affect the regulation of the prion protein gene. Recent in vivo and in vitro studies have suggested a role for prion protein in copper homeostasis. Copper can also induce prion gene expression in rat neurons. However, the mechanism involved in this regulation remains to be determined. We hypothesized that transcription factors SP1 and metal transcription factor-1 (MTF-1) may be involved in copper-mediated regulation of human prion gene. To test the hypothesis, we utilized human fibroblasts that are deleted or overexpressing the Menkes protein (MNK), a major mammalian copper efflux protein. Menkes deletion fibroblasts have high intracellular copper, whereas Menkes overexpressed fibroblasts have severely depleted intracellular copper. We have utilized this system previously to demonstrate copper-dependent regulation of the Alzheimer amyloid precursor protein. Here we demonstrate that copper depletion in MNK overexpressed fibroblasts decreases cellular prion protein and PRNP gene levels. Conversely, expression of transcription factors SP1 and/or MTF-1 significantly increases prion protein levels and up-regulates prion gene expression in copper-replete MNK deletion cells. Furthermore, siRNA "knockdown" of SP1 or MTF-1 in MNK deletion cells decreases prion protein levels and down-regulates prion gene expression. These data support a novel mechanism whereby SP1 and MTF-1 act as copper-sensing transcriptional activators to regulate human prion gene expression and further support a role for the prion protein to function in copper homeostasis. Expression of the prion protein is a vital component for the propagation of prion diseases; thus SP1 and MTF-1 represent new targets in the development of key therapeutics toward modulating the expression of the cellular prion protein and ultimately the prevention of prion disease.

Received for publication, June 23, 2008 , and in revised form, November 5, 2008.

^* This work was supported in part by a National Health and Medical Research Council Program grant (to A. F. H. and C. L. M.) and an Australian Research Council discovery grant (to S. A. B.). A.F.H. is a shareholder in and consultant to D-Gen Limited, an academic spin-out company working in the field of prion disease diagnosis, therapeutics, and decontamination. D-Gen markets the ICSM18 antibody used in this study. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

¹ Supported in part by the Australian Research Council Discovery Indigenous Research Cadetship.

² Supported by a National Health and Medical Research Council R. D. Wright Career Development Award (Level II). To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria 3010, Australia. Fax: 61-3-9348-1421; E-mail: a.hill{at}unimelb.edu.au.

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