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An Androgen-Dependent Upstream Enhancer Is Essential for High Levels of Probasin Gene Expression

Departments of Urologic Surgery (J.F.Z., N.G., S.K., R.J.M.), Cell and Developmental Biology (J.F.Z., N.G., S.K., R.J.M.), and Cancer Biology (S.K., R.J.M.), The Vanderbilt Prostate Cancer Center (S.K., R.J.M.), and The Vanderbilt-Ingram Cancer Center (S.K., R.J.M.), Vanderbilt University Medical Center, Nashville, Tennessee 37232-2765; and The Prostate Centre (K.R., C.N.), The Jack Bell Research Centre, Vancouver, British Columbia, Canada V6H 3Z6

Address all correspondence and requests for reprints to: Robert J. Matusik, Ph.D., Department of Urologic Surgery, A-1302 Medical Center North, Vanderbilt University Medical Center, Nashville, Tennessee 37232-2765. E-mail: robert.matusik{at}vanderbilt.edu.

Previously we reported that a small rat probasin (PB) promoter (-426 to +28 bp, -426PB) would target androgen- regulated prostate-specific expression in transgenic mice. Later we demonstrated that a large (L) fragment (-10806 to +28 bp, LPB) of the PB promoter would target high levels of gene expression to the prostate in transgenic mice. These results suggested that optimal transcription of the PB gene depended on the presence of enhancer regions upstream of the proximal promoter. To identify these enhancers, the LPB fragment was sequenced and the enhancer activities of restriction fragments were characterized in cell lines. Two nonconventional androgen receptor binding sites (ARBSs), ARBS-3 and ARBS-4, in an upstream androgen-dependent enhancer of the PB gene were identified. One site functions as a weak steroid response element in both LNCaP and MCF-7 cells; another site acts as a strong steroid response element, which preferentially responds to androgen and is preferentially activated in LNCaP cells. These two new ARBSs interact in a cooperative manner with the previously described androgen response region (ARR) (defined by -244 to -96 bp) that contains ARBS-1; ARBS-2; and two lower-affinity ARR binding sites, G-1 and G-2 sites. We conclude that the context in which the ARR binding sites are present is pivotal in determining their effect on transcriptional regulation. Thus, the -705/+28 PB promoter contains a second ARR, PB enhancer element (-705/-426 PB), in addition to the first described ARR. The PB promoter creates a model that contains six AR binding sites that function in a cooperative manner for maximum androgen-regulated prostate-specific gene transcription.

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