Gene expression, retinoids vitamin

Nuclear hormone receptors, including those for the principal classes of steroids, retinoids, vitamin D, and thyroid hormones, are transcription factors that influence gene expression. 

Retinoids are a family of naturally occurring and synthetic analogues of vitamin A. The skin of subjects deficient in vitamin A becomes hyperplastic and keratotic (phrynoderma, or toad skin). While natural vitamin A is occasionally employed therapeutically, synthetic retinoids are more effective and represent a major advance in dermatological pharmacotherapy. Retinoids have myriad effects on cellular differentiation and proliferation it is likely that nuclear retinoic acid receptors mediate these effects by activating gene expression in a manner analogous to receptors for steroid hormones and thyroid hormones. Despite a common mechanism of action, however, retinoids vary widely in their physiological effects. 

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. 

FIGURE 12-40 General mechanism by which steroid and thyroid hormones, retinoids, and vitamin D regulate gene expression. The details of transcription and protein synthesis are discussed in Chapters 26 and 27. At least some steroids also act through plasma membrane receptors by a completely different mechanism. 

Steroid, vitamin D, retinoid, and thyroid hormones enter target cells and alter gene expression by interacting with specific nuclear receptors. 

The form of vitamin A that is needed for regulating vitamin A-dependent gene expression is retinoic acid.All-fraws-retinoic acid can interact with each of the three RARs (RARa, RAR(3, and RARy) and each of the three RXRs (RXRa, RXR(3, and RXRy). 9-cX-Retinoic acid binds and effectively transactivates only the RXRs. The RARs and the RXRs recognize well-defined exacting response elements, termed retinoic acid response elements (RAREs) and retinoid X response elements (RXREs) that are present in the promoter regions of responsive genes. The RARs and RXRs bind to RAREs and/or RXREs as dimers, either homodimers or heterodimers. 

Retinoic acid modulates gene expression and tissue differentiation, acting by way of nuclear receptors. Historically, there was confusion between the effects of deficiency of vitamins A and D by the 1950s, it was believed that the confusion had been resolved. Elucidation of the nuclear actions of the two vitamins has shown that, in many systems, the two act in concert, forming retinoid-vitamin D heterodimeric receptors hypervitaminosis A can antagonize the actions of vitamin D. 

FIGURE 12-40 General mechanism by which steroid and thyroid hormones, retinoids, and vitamin D regulate gene expression. The de-... 

The retinoids comprise a family of polyisoprenoid lipids that inclndes vitamin A (retinol) and stracturaUy related componnds. The biological activity of retinoids can be mod-ihed, for example, by changes in the molecules state of oxidation and cis/trans isomerization. Their activity is also dependent on the levels of specific types of retinoid-binding proteins that exist in extracellular, cytosolic, and nuclear compartments. The role of retinoids in gene expression represents an important biological function for this family of molecules. Retinoid-dependent modulation of gene expression is critical for normal cell and tissue function in mature as well as developing animals. 

Recently, this system was used to identify several factors putatively involved in the mechanism of steroid hormone-mediated gene transcription. In a two-hybrid screen to identify factors that interact with the vitamin D receptor (VDR), we isolated transcription factor IIB (TFIIB) as a VDR-mteractive clone (2). The interaction of VDR, retinoic-acid receptors and other steroid-hormone receptors with TFIIB may represent a fundamental step in the mechanism of transcription mediated by the nuclear-receptor family (3-5) The two-hybrid system has also identified several putative coactivator and corepressor proteins that contact retinoid receptors, thyroid receptors, vitamin D receptors, and other members of the nuclear-receptor family (6-9) Thus, the two-hybrid system is playing an instrumental role in the identification of factors involved in nuclear receptor-mediated gene expression This chapter discusses several procedures and strategies used to establish a two-hybrid system to examine proteins that interact with retinoid receptors, with the VDR, or with nuclear receptors in general. 

Vitamin Bg has a central role in amino acid metabolism as the coenzyme for a variety of reactions, including transamination and decarboxylation. It is also the coenzyme of glycogen phosphorylase and acts to modulate the activity of steroid and other hormones (including retinoids and vitamin D) that act by regulation of gene expression. 

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