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Department of Pathology Erasmus University 3000 DR Rotterdam, The Netherlands
Prostate-specific antigen (PSA) is expressed at a
high level in the luminal epithelial cells of the prostate and is
absent or expressed at very low levels in other tissues. PSA expression
can be regulated by androgens. Previously, two functional
androgen-response elements were identified in the proximal promoter of
the PSA gene. To detect additional, more distal control elements,
DNaseI-hypersensitive sites (DHSs) upstream of the PSA gene were mapped
in chromatin from the prostate-derived cell line LNCaP grown in the
presence and absence of the synthetic androgen R1881. In a region 4.8
to 3.8 kb upstream of the transcription start site of the PSA gene, a
cluster of three DHSs was detected. The middle DNAseI-hypersensitive
site (DHSII, at 
-4.2 kb) showed strong androgen responsiveness in
LNCaP cells and was absent in chromatin from HeLa cells. Further
analysis of the region encompassing DHSII provided evidence for the
presence of a complex, androgen-responsive and cell-specific enhancer.
In transient transfected LNCaP cells, PSA promoter constructs
containing this upstream enhancer region showed approximately 3000-fold
higher activity in the presence than in the absence of R1881. The core
region of the enhancer could be mapped within a 440-bp fragment. The
enhancer showed synergistic cooperation with the proximal PSA promoter
and was found to be composed of at least three separate regulatory
regions. In the center, a functionally active, high-affinity androgen
receptor binding site (GGAACATATTGTATC) could be identified. Mutation
of this element almost completely abolished PSA promoter activity.
Transfection experiments in prostate and nonprostate cell lines showed
largely LNCaP cell specificity of the upstream enhancer region,
although some activity was found in the T47D mammary tumor cell line.
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C. B. J. M. Cleutjens, K. Steketee, C. C. E. M. van Eekelen, J. A. G. M. van der Korput, A. O. Brinkmann, and J. Trapman Both Androgen Receptor and Glucocorticoid Receptor Are Able to Induce Prostate-Specific Antigen Expression, but Differ in Their Growth-Stimulating Properties of LNCaP Cells Endocrinology, December 1, 1997; 138(12): 5293 - 5300. [Abstract] [Full Text] [PDF]
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K. B. J .M. Cleutjens, H. A. G. M. van der Korput, C. C. Ehren-van Eekelen, R. A. Sikes, C. Fasciana, L. W. Chung, and J. Trapman A 6-kb Promoter Fragment Mimics in Transgenic Mice the Prostate-Specific and Androgen-Regulated Expression of the Endogenous Prostate-Specific Antigen Gene in Humans Mol. Endocrinol., August 1, 1997; 11(9): 1256 - 1265. [Abstract] [Full Text]
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F. Yeung, X. Li, J. Ellett, J. Trapman, C. Kao, and L. W. K. Chung Regions of Prostate-specific Antigen (PSA) Promoter Confer Androgen-independent Expression of PSA in Prostate Cancer Cells J. Biol. Chem., December 22, 2000; 275(52): 40846 - 40855. [Abstract] [Full Text] [PDF]
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G. W. Verhaegh, A. van Bokhoven, F. Smit, J. A. Schalken, and M. J. G. Bussemakers Isolation and Characterization of the Promoter of the Human Prostate Cancer-specific DD3 Gene J. Biol. Chem., November 22, 2000; 275(48): 37496 - 37503. [Abstract] [Full Text] [PDF]
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F. Yeung, W. K. Law, C.-H. Yeh, J. J. Westendorf, Y. Zhang, R. Wang, C. Kao, and L. W. K. Chung Regulation of Human Osteocalcin Promoter in Hormone-independent Human Prostate Cancer Cells J. Biol. Chem., January 18, 2002; 277(4): 2468 - 2476. [Abstract] [Full Text] [PDF]
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C. E. Petre, Y. B. Wetherill, M. Danielsen, and K. E. Knudsen Cyclin D1: Mechanism and Consequence of Androgen Receptor Co-repressor Activity J. Biol. Chem., January 11, 2002; 277(3): 2207 - 2215. [Abstract] [Full Text] [PDF]
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S. Yeh, Y.-C. Hu, M. Rahman, H.-K. Lin, C.-L. Hsu, H.-J. Ting, H.-Y. Kang, and C. Chang Increase of androgen-induced cell death and androgen receptor transactivation by BRCA1 in prostate cancer cells PNAS, October 10, 2000; 97(21): 11256 - 11261. [Abstract] [Full Text] [PDF]
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