Cooperation and Competition Between Couptf and HNF4

COUP-TF (chicken ovalbumin upstream promoter-transcription factor) and HNF-4 were both frequently called orphan members of the steroid/thyroid receptor super-family and exhibit ubiquitous and liver-enriched tissue distribution, respectively (Ki-mura et al., 1993). COUP-TFs strongly inhibit transcriptional activation mediated by nuclear hormone receptors, including HNF-4. COUP-TFs repress HNF-4-dependent gene expression by competition with HNF-4 for common binding sites found in several regulatory regions (Kimura et al., 1993; Ktistaki and Talianidis, 1997b). In contrast, promoters such as the HNF-1 promoter, which are recognized by HNF-4 but not by COUP-TFs, are activated by COUP-TFI and COUP-TFII in conjunction with HNF-4 more than 100-fold above basal levels, as opposed to about 8-fold activation by HNF-4 alone (Ktistaki and Talianidis, 1997b). This enhancement was strictly dependent on an intact HNF-4 E domain. In-vitro and in vivo evidence suggests that COUP-TFs enhance HNF-4 activity by a mechanism that involves their physical interaction with the amino acid 227-271 region of HNF-4 (see also Figure 14.1) (Ktistaki and Talianidis, 1997b). Therefore, in certain promoters, COUP-TFs act as auxiliary cofactors for HNF-4, orienting the HNF-4 activation domain in a more efficient configuration to achieve enhanced transcriptional activity (Kimura et al., 1993; Ktistaki and Talianidis, 1997b). An example of COUP-TF-associated repression of a liver-specific gene is that of the gene for rat ornithine transcarbamylase, an ornithine cycle enzyme (Kimura et al., 1993). Therefore, COUP-TF plays a dual regulatory role depending on the promoter context. Repression of a tissue-specific promoter by a ubiquitous trans-activator and derepression by a related tissue-enriched trans-activator is potentially an important mechanism for tissue-specific activation of a gene (Kimura etal., 1993; Ktistaki and Talianidis, 1997b).

14.2.10

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