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FIGURE 1-44 Evaluation of the transcriptional activity of mutants of the human glucocorticoid receptor (A), the carboxy-terminal end, and (B) the amino-terminal end of the receptor. The top of each panel shows the intact glucocorticoid receptor with 777 amino acids. Each of the domains is indicated: open box (IMM), the immunogenic region; solid black rectangles, the DNA-binding domain; stipples, the ligand-binding domain. The receptor constructs of panels A and B are prepared via site-directed mutagenesis. In (A), where truncation mutants are evaluated, the numbers with asterisks indicate the last amino acid of the receptor before the COOH-terminal nonsense peptide. In (B), where deletion mutants are evaluated, the numbers indicate amino acids bounding the deletion. These mutant receptors were constructed via standard, but complex,

FIGURE 1-45 Illustration of homodimer and heterodimer interactions of the retinoic acid receptors. The retinoic acid receptors (RAR) exist in ai, ft, and y, isoforms and in the more distantly related RXR gene. Thus, four functional forms of the retinoic acid receptor are generated: RAR„ RAR,,, and RARy, which all preferentially bind as ligands to the trans form of retinoic acid, 9 trans-RA, and the RXR„ RXR,a, and RXRy receptors, which bind to the cis form of retinoic acid, 9-cis-RA. Interestingly, while RAR„ RAR^, and RAR, are only found in vertebrates, the RXR isoforms has been conserved from Drosophila to humans. The RXR receptor isoform species can interact with itself to generate the homodimer RXR. .RXR; the receptor ligand is exclusively 9-cis-RA. The RXR with its ligand 9-cis-RA can form heterodimers with each of the RAR species (which have 9-trans-RA as a ligand). Finally, RXR can also form heterodimers with the thyroxine (TR), l,25(OH)2D3 (VDR), or (postulated) receptors (indicated as XYZ). Collectively, this model suggests that RXR receptors have multiple central functions that allow the selective control of several nuclear hormone receptors as a consequence of heterodimer formation. [Modified from Zhang, X. and Pfahl, M. (1993). Hetero-and homodimeric receptors in thyroid hormone and vitamin A action. Receptor 3, 183-191.]

RxRa, RxR3, and RxRy

FIGURE 1-45 Illustration of homodimer and heterodimer interactions of the retinoic acid receptors. The retinoic acid receptors (RAR) exist in ai, ft, and y, isoforms and in the more distantly related RXR gene. Thus, four functional forms of the retinoic acid receptor are generated: RAR„ RAR,,, and RARy, which all preferentially bind as ligands to the trans form of retinoic acid, 9 trans-RA, and the RXR„ RXR,a, and RXRy receptors, which bind to the cis form of retinoic acid, 9-cis-RA. Interestingly, while RAR„ RAR^, and RAR, are only found in vertebrates, the RXR isoforms has been conserved from Drosophila to humans. The RXR receptor isoform species can interact with itself to generate the homodimer RXR. .RXR; the receptor ligand is exclusively 9-cis-RA. The RXR with its ligand 9-cis-RA can form heterodimers with each of the RAR species (which have 9-trans-RA as a ligand). Finally, RXR can also form heterodimers with the thyroxine (TR), l,25(OH)2D3 (VDR), or (postulated) receptors (indicated as XYZ). Collectively, this model suggests that RXR receptors have multiple central functions that allow the selective control of several nuclear hormone receptors as a consequence of heterodimer formation. [Modified from Zhang, X. and Pfahl, M. (1993). Hetero-and homodimeric receptors in thyroid hormone and vitamin A action. Receptor 3, 183-191.]

FIGURE 1-44—Continued molecular biological manipulations and inserted in plasmids. CV-1 cells that have no constitutive expression of steroid receptors were transfected with the receptor construct incorporated into a plasmid. The activity of the receptor constructs was monitored by their ability to induce transcription from a mouse mammary tumor virus (MMTV ^chloramphenicol acetyl transace-tylase (CAT) fusion gene also resident in the CV-I cells. The MMTV is known to have a specific HRE for the human glucocorticoid receptor; thus, a functional glucocorticoid receptor construct would activate the MMTV-CAT gene. This is expressed in each panel as CAT activity (%). In both (A) and (B), the CAT activity of the CV-I cells containing each receptor construct was determined in the presence (+DEX) and absence (-DEX) of dexamethasone. In A and B the constructs are numbered from top to bottom 1 —» 9. In (A), the essential nature of the DNA-binding domain is demonstrated; compare the CAT activity of construct (1) with the intact receptor; constructs (2) and (3) suggest, in the absence of the ligand-binding domain, that the receptor can function constitutively. Construct (9) demonstrates that a full ligand-binding domain is necessary for full hormone-dependent CAT activity. In (B), constructs (1-6) demonstrate the contribution of the IMM domain to creating a fully functional receptor. Construct (7) is analogous to construct (9) of (B), except that the region deleted is smaller (leaving the domain labeled A); thus, the panel A construct (7) is a fully active version of the receptor that can function even in the absence of ligand. [Reproduced with permission from Hollenberg, S. M., Giguere, V., Segui, P., and Evans, R. M. (1987). Co-localization of DNA-binding and transcriptional activation functions in the human glucocorticoid receptors. Cell 49, 39-46.]

of the retinoic acid receptors. The structure of the ligand of the RXR receptor, namely, 9-cis-retinoic acid, is given in Figure 1-46. It is not yet possible to understand in detail the outcome of the operation of these receptor heterodimers, although it seems likely that

9-frans-retinoic acid

FIGURE 1-46 Structures of retinol (vitamin A), 9-frans-retinoic acid, and 9-ris-retinoic acid.

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