|[Frontiers in Bioscience 1, d59-71, March 1, 1996]|
THE ANDROGEN RECEPTOR: A MEDIATOR OF DIVERSE RESPONSES
Evan T. Keller, William B. Ershler, and Chawnshang Chang
The Institute on Aging and the Department of Human Oncology, University of Wisconsin, Madison, WI 53706, USA.
Received 01/16/96; Accepted 02/22/96; On-line 03/01/96
As mentioned above, AR binds to the consensus ARE to induce the androgens' effects. However, several non-consensus ARE have also been reported in rat genes. The rat probasin gene contains a 17 bp non-consensus ARE (ARE-2) consisting of 5'-GTAAAGTACTCCAAGAA-3' (91). This element is located within the 5'-UTR and is approximately 100 bp downstream of a consensus ARE. Even though both the non-consensus and consensus elements bind AR, neither is an effective independent enhancer when tested with a heterologous thymidine kinase promoter. However, when they are both present in the same construct, a marked response to androgen is observed (91). The androgen-regulated 20-kD protein gene, which consists of four exons that code for a major secretory protein of rat ventral prostate, contains both consensus and non-consensus ARE (92). These are present in the first intron (In-1) and when CV1 cells were cotransfected with either GR or AR, In-1 and its most active subfragment, In-1c functioned as AREs but not as GRE (92). This effect was diminished in PC-3 and HeLa cells suggesting that other transcriptional factors may confer AR specificity to the non-consensus ARE. The human glandular kallikrein-1 gene (hKLK-2) contains an ARE in its 5' promoter region consisting of 5'-GGAACAGCAAGTGCT-3' (93). Deletion of the promoter immediately 5' to the non-consensus ARE resulted in a decreased induction of CAT activity (93). This suggests that the non-consensus ARE activity may be dependent on the interaction of AR with transcription factors which may bind to these upstream sequences.
In summary, it is likely that AR interaction with non-consensus ARE may depend on the interaction with other transcription factors which bind to cis-acting DNA elements in close proximity to the ARE. The existence of non-consensus ARE may allow androgen:AR complexes to expand their transactivating action. Thus, in conjunction with the classical AREs of androgen responsive genes, the non-consensus ARE may provide a degree of variability for the control of hormonal responses. Further identification and characterization of non-consensus ARE will provide additional clues as to how these elements participate in gene regulation.