Transcriptional Activation of the Nuclear Receptor Corepressor RIP140 by Retinoic Acid: A Potential Negative-Feedback Regulatory Mechanism

2001 ◽  
Vol 285 (4) ◽  
pp. 969-975 ◽  
Author(s):  
Joanna S. Kerley ◽  
Shannon L. Olsen ◽  
Sarah J. Freemantle ◽  
Michael J. Spinella
Keyword(s):  
Retinoic Acid ◽  
Nuclear Receptor ◽  
Negative Feedback ◽  
Transcriptional Activation ◽  
Regulatory Mechanism ◽  
Nuclear Receptor Corepressor ◽  
Feedback Regulatory Mechanism

scholarly journals Novel Mechanism of Nuclear Receptor Corepressor Interaction Dictated by Activation Function 2 Helix Determinants

2002 ◽  
Vol 22 (19) ◽  
pp. 6831-6841 ◽  
Author(s):  
Anna N. Moraitis ◽  
Vincent Giguère ◽  
Catherine C. Thompson
Keyword(s):  
Retinoic Acid ◽  
Thyroid Hormone ◽  
Ligand Binding ◽  
Nuclear Receptor ◽  
Thyroid Hormone Receptor ◽  
Activation Function ◽  
Binding Domain ◽  
Ligand Binding Domain ◽  
Cerebellar Development ◽  
Nuclear Receptor Corepressor

ABSTRACT Transcriptional regulation by nuclear receptors is controlled by the concerted action of coactivator and corepressor proteins. The product of the thyroid hormone-regulated mammalian gene hairless (Hr) was recently shown to function as a thyroid hormone receptor corepressor. Here we report that Hr acts as a potent repressor of transcriptional activation by RORα, an orphan nuclear receptor essential for cerebellar development. In contrast to other corepressor-nuclear receptor interactions, Hr binding to RORα is mediated by two LXXLL-containing motifs, a mechanism associated with coactivator interaction. Mutagenesis of conserved amino acids in the ligand binding domain indicates that RORα activity is ligand-dependent, suggesting that corepressor activity is maintained in the presence of ligand. Despite similar recognition helices shared with coactivators, Hr does not compete for the same molecular determinants at the surface of the RORα ligand binding domain, indicating that Hr-mediated repression is not simply through displacement of coactivators. Remarkably, the specificity of Hr corepressor action can be transferred to a retinoic acid receptor by exchanging the activation function 2 (AF-2) helix. Repression of the chimeric receptor is observed in the presence of retinoic acid, demonstrating that in this context, Hr is indeed a ligand-oblivious nuclear receptor corepressor. These results suggest a novel molecular mechanism for corepressor action and demonstrate that the AF-2 helix can play a dynamic role in controlling corepressor as well as coactivator interactions. The interaction of Hr with RORα provides direct evidence for the convergence of thyroid hormone and RORα-mediated pathways in cerebellar development.

scholarly journals Recruitment of Nuclear Receptor Corepressor and Coactivator to the Retinoic Acid Receptor by Retinoid Ligands

2000 ◽  
Vol 275 (25) ◽  
pp. 19401-19408 ◽  
Author(s):  
Elliott S. Klein ◽  
Jenny W. Wang ◽  
Berket Khalifa ◽  
Stacey A. Gavigan ◽  
Roshantha A. S. Chandraratna
Keyword(s):  
Retinoic Acid ◽  
Nuclear Receptor ◽  
Retinoic Acid Receptor ◽  
Acid Receptor ◽  
Nuclear Receptor Corepressor

scholarly journals LIM protein Ajuba functions as a nuclear receptor corepressor and negatively regulates retinoic acid signaling

2010 ◽  
Vol 107 (7) ◽  
pp. 2938-2943 ◽  
Author(s):  
Z. Hou ◽  
H. Peng ◽  
D. E. White ◽  
D. G. Negorev ◽  
G. G. Maul ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Nuclear Receptor ◽  
Retinoic Acid Signaling ◽  
Lim Protein ◽  
Nuclear Receptor Corepressor

scholarly journals Natural vitamin D3 response elements formed by inverted palindromes: polarity-directed ligand sensitivity of vitamin D3 receptor-retinoid X receptor heterodimer-mediated transactivation.

1995 ◽  
Vol 15 (3) ◽  
pp. 1154-1161 ◽  
Author(s):  
M Schräder ◽  
S Nayeri ◽  
J P Kahlen ◽  
K M Müller ◽  
C Carlberg
Keyword(s):  
Retinoic Acid ◽  
Nuclear Receptor ◽  
Vitamin D3 ◽  
Transcriptional Activation ◽  
Thyroid Hormone Receptor ◽  
Retinoid X Receptor ◽  
Direct Repeats ◽  
Response Element ◽  
Response Elements ◽  
Ligand Sensitivity

VDR, the nuclear receptor for 1,25-dihydroxyvitamin D3 (VD), is a member of the superfamily of nuclear hormone receptors and controls multiple aspects of homeostasis, cell growth, and differentiation. VDR can function as a homodimer, but heterodimerization with the retinoid X receptor (RXR), retinoic acid receptor, or thyroid hormone receptor increases its affinity for response elements in the promoter of target genes. All natural VD response elements identified so far consist of direct repeats of a variety of hexameric core binding motifs with a preferential spacing of three nucleotides (DR3s). However, all four VD signalling pathways function also on response elements formed by inverted palindromes, although these sequences were not of natural origin. Here, we report the identification of two VD response elements consisting of inverted palindromes spaced by nine nucleotides (IP9s) in the promoters of the human calbindin D9k gene and the rat osteocalcin gene. Like most DR3-type VD response elements, both IP9s are preferentially bound by VDR-RXR heterodimers with a 5'-RXR-VDR-3' polarity, whose transcriptional activity can be enhanced by costimulation with 9-cis retinoic acid. We demonstrate that changing the response element orientation relatively to the basal promoter decreases the sensitivity of transcriptional activation by VD by about 10-fold. Our findings indicate that inverted palindromes are as functional as direct repeats. Furthermore, we suggest that the orientation of a nuclear receptor complex in relation to the basic transcriptional machinery, which is directed by heterodimer polarity and response element orientation, influences the ligand sensitivity of the respective target gene expression.

scholarly journals Reduced Retinoic Acid-Sensitivities of Nuclear Receptor Corepressor Binding to PML- and PLZF-RARα Underlie Molecular Pathogenesis and Treatment of Acute Promyelocytic Leukemia

Blood ◽  
1998 ◽  
Vol 91 (8) ◽  
pp. 2634-2642 ◽  
Author(s):  
Fabien Guidez ◽  
Sarah Ivins ◽  
Jun Zhu ◽  
Mats Söderström ◽  
Samuel Waxman ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Fusion Protein ◽  
Histone Deacetylase ◽  
Acute Promyelocytic Leukemia ◽  
Nuclear Receptor ◽  
Histone Deacetylase Inhibitors ◽  
Promyelocytic Leukemia ◽  
Molecular Pathogenesis ◽  
Wild Type ◽  
Nuclear Receptor Corepressor

Typical acute promyelocytic leukemia (APL) is associated with expression of the PML-RARα fusion protein and responsiveness to treatment with all-trans retinoic acid (ATRA). A rare, but recurrent, APL has been described that does not respond to ATRA treatment and is associated with a variant chromosomal translocation and expression of the PLZF-RARα fusion protein. Both PML- and PLZF-RARα possess identical RAR sequences and inhibit ATRA-induced gene transcription as well as cell differentiation. We now show that the above-mentioned oncogenic fusion proteins interact with the nuclear receptor corepressor N-CoR and, in comparison with the wild-type RARα protein, their interactions display reduced sensitivities to ATRA. Although pharmacologic concentration of ATRA could still induce dissociation of N-CoR from PML-RARα, it had a very little effect on its association with the PLZF-RARα fusion protein. This ATRA-insensitive interaction between N-CoR and PLZF-RARα was mediated by the N-terminal PLZF moiety of the chimera. It appears that N-CoR/histone deacetylase corepressor complex interacts directly in an ATRA-insensitive manner with the BTB/POZ-domain of the wild-type PLZF protein and is required, at least in part, for its function as a transcriptional repressor. As the above-noted results predict, histone deacetylase inhibitors antagonize oncogenic activities of the PML-RARα fusion protein and partially relieve transcriptional repression by PLZF as well as inhibitory effect of PLZF-RARα on ATRA response. Taken together, our results demonstrate involvement of nuclear receptor corepressor/histone deacetylase complex in the molecular pathogenesis of APL and provide an explanation for differential sensitivities of PML- and PLZF-RARα–associated leukemias to ATRA.

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