Repressor of gene expression

In the presence of all- trans- or 9-ds-retinoic acid, the receptor heterodimers are transcriptional activators. However, the heterodimers will also bind to DNA in the absence of retinoic acid, in which case they act as repressors of gene expression (Fujita and Mitsuhashi, 1999). 

The normal form of interaction between receptor and DNA requires the hormone to have broken the native structure of the receptor and the dimer to have been formed. That is to say, the receptor-DNA interaction comes after the hormone-receptor interaction. Nevertheless, situations have been described in vitro in which the receptor is able to be previously associated to the HRE. This situation occurs in vivo for the thyroid hormone receptors, in which case it seems that the hormone-free dimer acts as an expression repressor of genes dependent on these hormones (Evans et al. 1988). The arrival of the hormone activates the dimer in situ and inverts its role as regulator. 

Activator proteins (and a few repressors) are important in eukaryotes, as they are in prokaryotes. The DNA sequences to which activator proteins bind in eiikaryotic DNA are called response elements. A few response elements are located within the promoter region (upstream promoter elements [UPE]), but most are outside the promoter and often clustered to form an enhancer region that allows control of gene expression by multiple signals (Figure 1-5-4). 

A further significant mechanism of transcription control is the repression of gene expression (review Cowell, 1994 Johnson, 1995). There are two types of gene repression to be distinguished in eucaryotes. On the one hand the chromatin structure can cause an unspecific repression of gene expression (see 1.4.6). On the other hand, analogous to the specific transcriptional activators, there are specific repressors of transcription. Their effect, in contrast to that of vmspecific repressors, is sequence-dependent and thus suitable for selective repression (Fig. 1.40). DNA sequences that mediate repression of transcription factors are termed silencers. 

A further, more dramatic difference to the steroid hormone receptors is the localization of the receptors. The receptors for the retinoids (RAR and RXR, see table 4.1), the T3 hormone (T3R) and vitamin D3 (VDR) are mainly localized in the nucleus and their activity is not controlled by the heat shock proteins. The receptors also bind the corresponding HRE in the absence of hormone, in which case they can then act as repressors of gene activity. In the presence of the hormone an activation of gene expression is usually observed. 

The mechanisms by which operons are regulated can vary significantly from the simple model presented in Figure 28-7. Even the lac operon is more complex than indicated here, with an activator also contributing to the overall scheme, as we shall see in Section 28.2. Before any further discussion of the layers of regulation of gene expression, however, we examine the critical molecular interactions between DNA-binding proteins (such as repressors and activators) and the DNA sequences to which they bind. 

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