Transactivation properties of retinoic acid and retinoid X receptors in mammalian cells and yeast. Correlation with hormone binding and effects of metabolism.

Allegretto, Elizabeth A.; McClurg, Michael; Lazarchik, Steven B.; Clemm, D L; Kerner, Sandra A.; Elgort, Marc G.; Boehm, Marcus F.; White, Steven K; Pike, J. Wesley; Heyman, Rich

doi:10.1016/s0021-9258(19)74358-0

Cited by 164 publications

(24 citation statements)

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“…The functional role of each monomer within RXRcontaining heterodimers is not clear at present. Potentially, heterodimerization of RAR and RXR can result in the convergence of signaling by two different retinoids: alltrans-retinoic acid (tRA), which binds to RAR, and 9cRA, which binds to both receptors (Levin et al, 1992;Heyman et al, 1992;Allenby et al, 1993;Allegretto et al, 1993). A number of studies indeed showed that in cells in which RXR and RAR are coexpressed, 9cRA is more effective in inducing transactivation than tRA regardless of the type of reporter construct used (Durand et al, 1992;Zhang et al, 1992;Heery et al, 1993;Lee et al, 1995;Chen et al, 1995).…”

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confidence: 99%

Individual Subunits of Heterodimers Comprised of Retinoic Acid and Retinoid X Receptors Interact with Their Ligands Independently

et al. 1996

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The retinoid X receptor (RXR) is a member of a family of transcription factors, known as hormone nuclear receptors, that mediate the effects of hydrophobic hormones on gene transcription. RXR, which is activated by 9-cis-retinoic acid (9cRA), can modulate several signaling pathways by virtue of its ability to form heterodimers with other members of the receptor family, as, for example, the retinoic acid receptor (RAR). The roles of the individual receptors within heterodimers are not clear as yet. It was recently reported that heterodimerization inhibits transcriptional activation by RXR, an effect that was attributed to an inability of RXR within heterodimers to bind its ligand. This inhibition was reported to depend on the association of heterodimers with cognate DNA and on the level of saturation of the RAR subunit within the heterodimers. In the present work, the ligand-binding characteristics of RXR and RAR individually and within heterodimers were examined by fluorescence-based methods. The results indicate that heterodimerization with RAR does ot alter the ligand-binding capacity of RXR nor the rate of dissociation of the ligand from this receptor. The ligand-binding capacity of RXR also was not affected by association of heterodimers with cognate DNA nor by the level of saturation of the RAR subunit. The data indicate further that the affinity of RAR for 9cRA is considerably higher as compared to RXR and that this differential affinity is retained within RAR-RXR heterodimers. Thus, binding of ligands by subunits within RAR-RXR heterodimers proceeds independently.

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confidence: 99%

Individual Subunits of Heterodimers Comprised of Retinoic Acid and Retinoid X Receptors Interact with Their Ligands Independently

et al. 1996

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“…Panagonist specific for RAR, but not for RXR, can transform almost all vibrissae into glands RAR null mutants, and especially double knockout mutants, have a very reduced viability, thus impairing their use in a large series of grafting experiments. Furthermore, tRA may possibly transactivate the RXR through its isomerization (Heyman et al, 1992; Levin et al, 1992;Allegretto et al, 1993). We therefore used synthetic retinoids specific either for the RAR (the pan-RAR CD367) or for the RXR (the pan-RXR Ro25-7386) to discern the respective involvement of these two families of receptors in tRA induced glandular metaplasia.…”

Section: Rarγ Knockout Dramatically Decreases the Ratio Of Trainduced Glandular Metaplasiamentioning

confidence: 99%

“…RAR are the primary effectors of the upper-lip skin glandular metaplasia It is known that tRA can isomerize into 9-cis retinoic acid that binds RAR as well as RXR (Heyman et al, 1992;Levin et al, 1992;Allegretto et al, 1993); however, CD367, a pan-RAR with no effect onto RXR (Xiao et al, 1995), was able not only to induce the hair vibrissa metaplasia in all treated explants, but also to transform 100% of the vibrissae into glands and to produce a SG hyperplasia, strongly suggesting that the RAR are the primary effectors of vibrissa metaplasia. That tRA treatment never gives rise to a SG hypertrophy may possibly arise from its rapid metabolism in vivo.…”

Section: Genotypementioning

confidence: 99%

“…RAR null mutants, and especially double knockout mutants, have a very reduced viability, and thus are very difficult to obtain in large numbers. Furthermore, tRA may possibly transactivate the RXR through isomerization (Heyman et al, 1992;Levin et al, 1992;Allegretto et al, 1993). We therefore used synthetic retinoids specific either for the RAR or for the RXR to discern the respective involvement of these receptors in tRA induced glandular metaplasia.…”

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confidence: 99%

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Both Retinoic Acid Receptors α (RARα) and γ (RARγ) Are Able to Initiate Mouse Upper-Lip Skin Glandular Metaplasia

Blanchet

Favier

Chevalier

et al. 1998

Journal of Investigative Dermatology

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Embryonic mouse upper-lip skin explants treated with 16.7 microM all-trans retinoic acid (tRA) give rise to a glandular metaplasia of hair vibrissa follicles; however, at this concentration, tRA can activate not only the three retinoic acid receptors (RARalpha, beta, and gamma), but also the retinoid X receptors (RXRalpha, beta, and gamma) as a consequence of its isomerization to 9-cis retinoic acid. We therefore studied the respective roles of the RXR and RAR by treating RARalpha(-/-), beta(-/-), and gamma(-/-) skin explants with tRA and wild-type explants with synthetic retinoids specific for RXR or for each of the RAR. The null mutation of the RARalpha, RARbeta, and RARgamma genes did not prevent tRA-induced hair glandular metaplasia, but RARgamma inactivation dramatically reduced its ratio. As demonstrated by treating explants with a RAR- or a RXR-specific panagonist (CD367 and Ro25-7386, respectively), RAR are primarily responsible for this metaplasia. The use of two retinoids (Ro40-6055, 8 x 10(-3) microM, or CD437, 7.7 x 10(-2) microM) that are believed to act, respectively, as a RARalpha- or a RARgamma-specific agonist showed that both these receptors can initiate a metaplasia. In contrast, BMS453, a RARbeta-specific agonist, was unable to give rise to any metaplasia. Nevertheless, the highest degrees and ratios of metaplasia were only obtained after treatment with the CD367 RAR panagonist, or with either Ro40-6055 or CD437 at a concentration sufficient to allow the activation of the three RAR, suggesting that RARbeta activation is required for a metaplasia of all vibrissae.

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“…Multiple libraries were designed by various groups based on the hypothesis that binding affinity arises from hydrophobic contacts and that specificity arises from binding pocket size, shape, hydrogen bonding, and electrostatics. The targeted residues to be exchanged were chosen based on their proximity to the bound ligand as observed in the crystal structure [161][162][163].…”

Section: Rational Designmentioning

confidence: 99%

Development of an orthogonal ligand-receptor pair based on synthetic estrogen analogs and engineered estrogen receptor for transcriptional regulation

Islam¹

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Transactivation properties of retinoic acid and retinoid X receptors in mammalian cells and yeast. Correlation with hormone binding and effects of metabolism.

Cited by 164 publications

References 50 publications

Individual Subunits of Heterodimers Comprised of Retinoic Acid and Retinoid X Receptors Interact with Their Ligands Independently

Individual Subunits of Heterodimers Comprised of Retinoic Acid and Retinoid X Receptors Interact with Their Ligands Independently

Both Retinoic Acid Receptors α (RARα) and γ (RARγ) Are Able to Initiate Mouse Upper-Lip Skin Glandular Metaplasia

Development of an orthogonal ligand-receptor pair based on synthetic estrogen analogs and engineered estrogen receptor for transcriptional regulation

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