Retinoids gene activation

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 discovery of nuclear RARs has introduced a novel method for evaluating the potential carcinostatic activity of a new retinoid [81,84-88], This can be done by measuring the ability of a retinoid either to bind to the RARs [84,85,87,88] or to induce activation of reporter genes via an RAR [81,86-88]. The affinity of retinoids for nuclear receptors in HL-60 cells appears to correlate well with anti-APL activity in vitro [94,95] as discussed in the next section. In general, a good correlation between retinoid carcinostatic activity and ability to bind to or activate retinoic acid receptors appears to exist. 

Target genes of retinoids and activation of the signalling cascade in human skin... 

In collaboration with the Pfahl group, we first reported that retinoid transcriptional activity depended on the RE used in the reporter construct [100, 101]. This finding has since been confirmed by another group [17]. Whether natural or synthetic, these REs are often repeated multiple times to enhance the transcriptional response. If the tertiary structure of this sequence differs from that found in natural gene sequences, the transcriptional response can be altered. Retinoid receptors are overexpressed in the cotransfection assay compared to their endogenous levels. Responses may differ because overexpressed receptor levels exceed the endogenous lev-... 

Retinoid antagonist activity is indicated if a retinoid binds to a retinoid receptor but is not able to induce the conformational change in the receptor LED AF-2 region of helix 12 necessary to release a corepressor and/or bind a coactivator protein [90,110] so that gene transcription on a retinoid RE is activated. Thus, the conformation of the receptor does not undergo the appro-... 

Proton Pump Inhibitors and Acid Pump Antagonists retinoid X receptor (RXR) and is also activated by various lipophilic compounds produced by the body such as bile acids and steroids. PXR heterodimerized with RXR stimulates the transcription of cytochrome P450 3A monooxygenases (CYP3A) and other genes involved in the detoxification and elimination of the... 

The concept of drug development is based on the findings that retinoid receptors (RARs and RXRs) offer a new approach by targeting different genes depending on the activated retinoid receptor complexes. The multiplicity of these retinoid signaling pathways affords potential for therapeutic opportunity as well as retinoid therapy associated undesired side effects. It is possible that the indiscriminate activation of all pathways by nonspecific retinoid ligands could lead to unacceptable side effects so that any enhanced efficacy would be obtained at the cost of enhanced toxicity. 

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