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J. Biol. Chem., Vol. 282, Issue 27, 19742-19752, July 6, 2007

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The Sterol Carrier Protein SCP-x/Pro-SCP-2 Gene Has Transcriptional Activity and Regulates the Alzheimer Disease -Secretase^*

Mi Hee Ko and Luigi Puglielli¹

From the Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin 53705 and the Geriatric Research Education Clinical Center, Veterans Affairs Medical Center, Madison, Wisconsin 53705

The sterol carrier protein SCP-x/pro-SCP-2 gene is a fusion gene having two initiation sites that generate a long (SCP-x; 58.9-kDa) and a short (pro-SCP-2; 15.4-kDa) product, both containing the common SCP-2 module at the C terminus. Here, we show that SCP-x is processed on the peroxisomal surface to liberate a short C-terminal product of 12.9 kDa. This fragment has DNA binding activity in vivo and in vitro, as assessed by chromatin immunoprecipitation analysis, DNA-protein pull-down, electrophoretic mobility shift assay, and luciferase reporter activity. In addition, it is preferentially found in the nucleus where it regulates the transcription of CD147, the regulatory subunit of the Alzheimer disease -secretase. Overexpression of SCP-x increased, whereas antisense oligonucleotides against scp-x decreased, the generation of the above transcription factor. Both biochemical and genetic approaches indicate that pro-SCP-2 acts as a competitive inhibitor of SCP-x processing, thereby controlling the release of the 12.9-kDa transcriptionally active fragment. The transcription regulatory function of pro-SCP-2 requires a peroxisomal targeting sequence at the C terminus and a 20-amino acid leading sequence at the N terminus. Finally, pro-SCP-2 has also cholesterol carrier activity, which is functionally separated from the transcription regulatory one. In conclusion, we have identified two novel functions (transcriptional and transcription regulatory) of the SCP-x/pro-SCP-2 gene that have impact on -secretase activity.

Received for publication, December 13, 2006 , and in revised form, May 1, 2007.

^* This work was supported by the University of Wisconsin Medical School's Medical Education and Research Committee through The Wisconsin Partnership Fund for a Healthy Future and by the Alzheimer Association. 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.

¹ To whom correspondence should be addressed: Dept. of Medicine, University of Wisconsin-Madison, VAH-GRECC 11G, 2500 Overlook Terrace, Madison, WI 53705. Tel.: 608-256-1901, (ext. 11569); Fax: 608-280-7291; E-mail: lp1{at}medicine.wisc.edu.

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