Glucocorticoids are involved in a wide array of physiological responses, including regulation of glucose, lipid, and protein metabolism, stress response, immune function, and mood (Tables 3.4, 3.5). Given the wide array of responses that these hormones (produced primarily by the adrenal gland) elicit, it is not surprising that the GR is expressed widely and that its function has been extensively explored. As discussed above (see Crosstalk Between Nuclear Receptors and Other Transcription Factors), analysis of bona fide target genes for GR has been complicated by the multiple mechanisms of transcriptional control that this receptor exhibits. For gluco-neogenic enzymes, the GR generally activates transcription through positively acting response elements. However, many of the actions of glu-cocorticoids are inhibitory, and this is partially achieved through binding to negative response elements within the promoters for genes such as prolactin and proopiomelanocortin. Most of the antiinflammatory effects of glucocorticoids involve another mechanism of repression, which does not seem to require the DBD of this receptor and probably involves protein-protein interactions of GR with subunits of the AP-1 and NF-kB transcription factors described earlier.283,312 Elegant studies evaluating the functional consequences of GR inac-tivation in mice demonstrate that GR function is essential for viability but that its DBD is indeed dispensable for most of these essential functions.313,314 This was demonstrated by comparing the phenotypes of animals that had homozygous null GR alleles with those that had wild-type alleles replaced by a mutant allele that prevented homodimerization and impaired DNA binding. The only phenotype common to the two mutant lines of mice was lack of GC-dependent induction of gluconeogenic enzymes, suggesting that many of the physiological functions of GRs are mediated by DNA-independent mechanisms of transcrip-tional regulation. As discussed previously, NRs probably acquired DNA-binding activity prior to ligand-binding activity during evolution. In this case, it seems that under certain physiological states, regulation of transcription by the LBD (i.e., cross-talk) supercedes the functionality of the DBD. As with several other NRs, two alternatively spliced mRNAs are generated from the GR gene, designated GRa and GRjS, which differ in length at the 3' end of the transcript. While the in vivo significance of expres sion of these isoforms has not been thoroughly explored, preliminary studies suggest that these isoforms have differential transcriptional activity and that truncated GRjS, which lacks an AF-2 region, functions as a dominant negative subunit.315
Mineralocorticoid receptors are primarily involved in the regulation of salt balance. In addition to being activated by the mineralocorti-coid aldosterone, MR binds to and is activated by glucocorticoids. Since MRs are expressed in many tissues that also express GRs, it is probable that MR also activates transcription through GREs.316,317 However, in tissues where MR function is critical, such as in the gut and kidney, glucocorticoids are metabolized via the action of 11jS-hydroxysteroid dehydrogenase, ensuring MR-aldosterone sensitivity.318 Currently, little is known about bona fide MR target genes, other than that loss of the receptor through gene knockout results in severely impaired regulation of salt balance.319 In any event, it is clear that the CNS-related activities of these two receptors ensure appropriate regulation of peptide and steroid hormone production and response from the hypothala-mic-pituitary-adrenal axis.
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