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J. Biol. Chem., Vol. 279, Issue 29, 30880-30887, July 16, 2004

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Identification of an Androgen Response Element in Intron 8 of the Sterol Regulatory Element-binding Protein Cleavage-activating Protein Gene Allowing Direct Regulation by the Androgen Receptor^*

Hannelore Heemers, Guy Verrijdt¶, Sophie Organe, Frank Claessens¶, Walter Heyns, Guido Verhoeven, and Johannes V. Swinnen||

From the Laboratory for Experimental Medicine and Endocrinology, Faculty of Medicine, Onderwijs en Navorsing, Gasthuisberg, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium and the ^¶Division of Biochemistry, Faculty of Medicine, Onderwijs en Navorsing, Gasthuisberg, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium

Sterol regulatory element-binding proteins (SREBPs) are transcription regulators that play a pivotal role in intracellular lipid homeostasis. They are synthesized as inactive precursor proteins in the endoplasmic reticulum, where they are retained by SREBP cleavage-activating protein (SCAP), a sterol sensing protein that in turn is linked to a retention protein complex. Low intracellular sterol concentrations weaken the interaction of SCAP with its retention proteins and allow translocation of the SREBP·SCAP complex to the Golgi compartment where SREBP is proteolytically cleaved and activated. Previous studies on the mechanisms by which androgens provoke a coordinated activation of lipogenic pathways in prostate cancer cells have suggested an alternative pathway of activation in which androgens increase the expression of SCAP and favor translocation of the SREBP·SCAP complex to the Golgi apparatus by disturbing the balance between SCAP and its retention proteins. Here we show that the SCAP gene contains an androgen-responsive region located in intron 8. This region interacts directly with the androgen receptor and confers androgen responsiveness to promoter-reporter constructs transfected in LNCaP cells. It contains a noncanonical androgen response element GGAAGAaaaTGTACC that interacts not only with the androgen receptor but also with the glucocorticoid receptor and that also confers glucocorticoid responsiveness. The identification of a steroid response element in intron 8 of the SCAP gene further supports the contention that SCAP is a direct target for steroid hormone action.

Received for publication, February 13, 2004 , and in revised form, May 3, 2004.

^* This work was supported by a grant from a Concerted Research action (Research Fund, Katholieke Universiteit Leuven), a grant and a postdoctoral fellowship (to G. V.) from the Fund for Scientific Research-Flanders, a Cancer Research grant from Fortis Bank Insurance, and a grant from the Interuniversity Attraction Poles Programme-Belgian Science Policy. 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.

Recipient of a specialization grant from the Institute for Encouragement of Innovation by Science and Technology in Flanders.

^|| To whom correspondence should be addressed: LEGENDO, Onderwijs en Navorsing, Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium. Tel.: 32-16-345974; Fax: 32-16-345934; E-mail: johan.swinnen{at}med.kuleuven.ac.be.

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