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https://hdl.handle.net/2440/73038
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Type: | Journal article |
Title: | Long terminal repeats act as androgen-responsive enhancers for the PSA-Kallikrein locus |
Author: | Lawrence, M. Stephens, C. Need, E. Lai, J. Buchanan, G. Clements, J. |
Citation: | Endocrinology, 2012; 153(7):3199-3210 |
Publisher: | Endocrine Soc |
Issue Date: | 2012 |
ISSN: | 0013-7227 1945-7170 |
Statement of Responsibility: | Mitchell G. Lawrence, Carson R. Stephens, Eleanor F. Need, John Lai, Grant Buchanan, and Judith A. Clements |
Abstract: | The androgen receptor (AR) signaling pathway is a common therapeutic target for prostate cancer, because it is critical for the survival of both hormone-responsive and castrate-resistant tumor cells. Most of the detailed understanding that we have of AR transcriptional activation has been gained by studying classical target genes. For more than two decades, Kallikrein 3 (KLK3) (prostate-specific antigen) has been used as a prototypical AR target gene, because it is highly androgen responsive in prostate cancer cells. Three regions upstream of the KLK3 gene, including the distal enhancer, are known to contain consensus androgen-responsive elements required for AR-mediated transcriptional activation. Here, we show that KLK3 is one of a specific cluster of androgen-regulated genes at the centromeric end of the kallikrein locus with enhancers that evolved from the long terminal repeat (LTR) (LTR40a) of an endogenous retrovirus. Ligand-dependent recruitment of the AR to individual LTR-derived enhancers results in concurrent up-regulation of endogenous KLK2, KLK3, and KLKP1 expression in LNCaP prostate cancer cells. At the molecular level, a kallikrein-specific duplication within the LTR is required for maximal androgen responsiveness. Therefore, KLK3 represents a subset of target genes regulated by repetitive elements but is not typical of the whole spectrum of androgen-responsive transcripts. These data provide a novel and more detailed understanding of AR transcriptional activation and emphasize the importance of repetitive elements as functional regulatory units. |
Keywords: | Cell Line, Tumor Centromere Epithelial Cells Humans Retroviridae Prostatic Neoplasms Kallikreins Prostate-Specific Antigen Receptors, Androgen Androgens Gene Expression Regulation, Neoplastic Gene Deletion Binding Sites Base Sequence Terminal Repeat Sequences Models, Biological Molecular Sequence Data Male |
Rights: | Copyright © 2012 by The Endocrine Society |
DOI: | 10.1210/en.2012-1267 |
Grant ID: | http://purl.org/au-research/grants/nhmrc/497270 http://purl.org/au-research/grants/nhmrc/1035721 http://purl.org/au-research/grants/arc/DP110101101 |
Published version: | http://dx.doi.org/10.1210/en.2012-1267 |
Appears in Collections: | Aurora harvest Medicine publications |
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