[Frontiers in Bioscience 1, d59-71, March 1, 1996]


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

7. How does a nonspecific steroid response element confer androgen specific action?

Characterization of the consensus ARE using the AR DNA binding domain (DBD) in a DNA binding-site selection assay revealed the consensus ARE to be identical to the consensus GRE (94). This finding, taken together with the observation that GR is nearly ubiquitous in cells elicits the question as how androgen specific action is mediated by the ARE. Several observations provide clues as to how specific action can be mediated from these apparently non-specific HREs. Many androgen responsive genes have promoters which consist of several regulatory elements which suggests that an androgen specific response may be due to a combination of interacting transcription factors. This control mechanism would allow for developmental and cell specific control of androgen response as is observed with the 20 kDa protein gene (92). That the receptor itself may interact differently at the same response element is suggested by the observation that even though the DBDs of members of the GR subfamily are highly conserved, the transactivation domains are not. Thus, even though GR and AR may bind to the same DNA element, they may invoke different activity on the promoter region. This is the case for the sex-limited protein (Slp) of the mouse (95). Slp is a murine serum protein of unknown function which is synthesized primarily in the liver of mature males or T-treated females. It is encoded by a gene (C4-slp) in the S region of the major histocompatability complex class III gene complex (95). Slp's androgen dependence has been attributed to an androgen-responsive promoter in the C4-slp gene. Hemenway et al. identified several DNAse I hypersensitive sites which appeared in the C4-slp promoter upon androgen treatment (96). An androgen responsive region was identified within a 750 bp fragment found 2-kb upstream of the transcription initiation site in the C4-slp promoter by Loreni et al. (97). This androgen-responsive enhancer was identified as a 5' long terminal repeat of an ancient provirus which is most likely a retrotransposon. Adler et al. delineated the androgen-responsive enhancer to a 160 bp fragment (98).

Even though both AR and GR can bind the HRE element in the context of the slp promoter, GR inhibits AR induction of the slp gene (99). Interestingly, the GR can activate a heterologous promoter (thymdine kinase promoter) when the slp HRE element itself is placed upstream of it. Additionally, when the HRE element is moved as little as 10 bases away from the enhancer region, GR can activate the promoter (100). These findings strongly support that the context of the HRE is important in determining the specificity of the steroid receptor response. In light of the multiple elements found in the promoter region, such specificity is most likely mediated by protein-protein interactions with accessory transcription factors. These factors either inhibit or are not sufficient for the GR-induced activation of the enhancer while they are permissive for the AR-induced activation. Differences in transactivation domains of the steroid receptors could account for the distinct interactions which occur with the accessory transcription factors.

Tissue specific expression of hormone receptors is another mechanism by which a steroid-specific response can be generated. Strahle et al. introduced a progesterone-receptor expression plasmid into the rat hepatoma cell line, Fto2B-3 which contains glucocorticoid receptor but is devoid of progesterone receptor (101). They observed that the expression of the progesterone receptor in Fto2B-3 cells rendered endogenous glucocorticoid-regulated genes inducible by progestins. This experiment demonstrated that the specificity of responsiveness by a HRE to a steroid receptor in cells can be reprogrammed by the expression of a different steroid receptor which is capable of binding the HRE in question.

In summary, steroid specific expression can be mediated at both the gene and cellular levels. At the gene level, the context of the HRE may be critical for orchestrating a specific steroid response. Response elements in the proximity of the HRE may provide binding sites for accessory transcription factors. These factors are required to generate activation of the enhancer and yet may only interact with a specific hormone receptor, generating the specificity of the steroid-induced gene activation. At the cellular level, tissue specific expression of steroid receptors will limit the steroid response only to those cognate receptors.

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