RXR and its Brothers
Transcription Factors

Author: Gianpiero Pescarmona
Date: 17/07/2011

Description

DEFINITION

The retinoid X receptor is a type of nuclear receptor that is activated by 9-cis retinoic acid.
There are three retinoic X receptors (RXR): RXR-alpha, RXR-beta, and RXR-gamma, encoded by the RXRA, RXRB, RXRG genes, respectively.
RXR heterodimerizes with subfamily 1 nuclear receptors including CAR, FXR, LXR, PPAR, PXR, RAR, TR, and VDR.
As with other type II nuclear receptors, the RXR heterodimer in the absence of ligand is bound to hormone response elements complexed with corepressor protein. Binding of agonist ligands to RXR results in dissociation of corepressor and recruitment of coactivator protein, which, in turn, promotes transcription of the downstream target gene into mRNA and eventually protein.

THE GENE

DatabaseLinkLinkLink
WikigenesRXRaRXRbRXRg
GeneCards"RXRa":"RXRb":"RXRg":
Your Favorite Gene Sigma"RXRa":"RXRb":"RXRg":

CHEMICAL STRUCTURE AND IMAGES

When relevant for the function

  • Primary structure
  • Secondary structure
  • Tertiary structure
  • Quaternary structure

Protein Aminoacids Percentage (Width 700 px)

SYNTHESIS AND TURNOVER

mRNA synthesis
protein synthesis

post-translational modifications
degradation

CELLULAR FUNCTIONS

cellular localization,
biological function

Retinoic acid signaling and the evolution of chordates, 2006
p=.

  • Enzymes
DatabaseLink
BRENDA - The Comprehensive Enzyme Information System"URL":
KEGG Pathways"URL":
Human Metabolome Database"URL":
  • Cell signaling and Ligand transport
  • Structural proteins

REGULATION

DIAGNOSTIC USE

RXR-alpha

1. FUNCTION: Nuclear hormone receptor. Involved in the retinoic acid response pathway. Binds 9-cis retinoic acid (9C-RA). ARF6 acts as a key regulator of the tissue-specific adipocyte P2 (aP2) enhancer (By similarity).
2. SUBUNIT: Homodimer or forms a heterodimer with peroxisome proliferator activated receptor gamma called adipocyte-specific transcription factor ARF6. Interacts with NCOA3 and NCOA6 coactivators, leading to a strong increase of transcription of target genes (By similarity). Interacts with SFPQ. Interacts with HCV core protein. Interacts with PELP1. Interacts with SENP6.
3. INTERACTION: O60869:EDF1; NbExp=1; IntAct=EBI-78598, EBI-781301; P55345:HRMT1L1; NbExp=1; IntAct=EBI-78598, EBI-78458; Q9JLI4:Ncoa6 (xeno); NbExp=1; IntAct=EBI-78598, EBI-286271;
4. SUBCELLULAR LOCATION: Nucleus.
5. TISSUE SPECIFICITY: Highly expressed in liver, also found in lung, kidney and heart.
6. DOMAIN: Composed of three domains: a modulating N-terminal domain, a DNA-binding domain and a C-terminal steroid-binding domain.
7. PTM: Sumoylated on Lys-108; which negatively regulates transcriptional activity. Desumoylated specifically by SENP6.
8. SIMILARITY: Belongs to the nuclear hormone receptor family. NR2 subfamily.
9. SIMILARITY: Contains 1 nuclear receptor DNA-binding domain.
10. WEB RESOURCE: Name=Wikipedia; Note=Retinoid X receptor entry; URL=

RXR-beta

  1. FUNCTION: Nuclear hormone receptor. Involved in the retinoic acid response pathway. Binds 9-cis retinoic acid (9C-RA).
  2. SUBCELLULAR LOCATION: Nucleus.
  3. ALTERNATIVE PRODUCTS: Event=Alternative splicing; Named isoforms=2; Comment=Additional isoforms seem to exist; Name=Long; IsoId=P28702-1; Sequence=Displayed; Name=Short; IsoId=P28702-2; Sequence=Not described;
  4. TISSUE SPECIFICITY: Expressed in a variety of tumor cell lines.
  5. DOMAIN: Composed of three domains: a modulating N-terminal domain, a DNA-binding domain and a C-terminal steroid-binding domain.
  6. SIMILARITY: Belongs to the nuclear hormone receptor family. NR2 subfamily.
  7. SIMILARITY: Contains 1 nuclear receptor DNA-binding domain

RXR molecular biology

Nuclear import

Nuclear Import of the Retinoid X Receptor, the Vitamin D Receptor, and Their Mutual Heterodimer 2005

RXR import to Mitochondria

RXR shortened form and mitochondrial uptake

Retinoid X receptor regulates Nur77/TR3-dependent apoptosis [corrected] by modulating its nuclear export and mitochondrial targeting. 2004

figure from: Endocrine regulation of mitochondrial activity: involvement of truncated RXRalpha and c-Erb Aalpha1 proteins. 2003

Limited Degradation of Retinoid X Receptor by Calpain 1996

Tumor necrosis factor-alpha-inducible IkappaBalpha proteolysis mediated by cytosolic m-calpain. A mechanism parallel to the ubiquitin-proteasome pathway for nuclear factor-kappab activation. 1999

Oxidative stress decreases G protein-coupled receptor kinase 2 in lymphocytes via a calpain-dependent mechanism. 1999

The parkinsonian neurotoxin rotenone activates calpain and caspase-3 leading to motoneuron degeneration in spinal cord of Lewis rats.

Using helix 3 and helix 12 mutants of VDR and
RXR, we provide functional evidence that liganded VDR allosterically modifies
RXR from an apo(unliganded)- to a holo(liganded)-receptor conformation, in the
absence of RXR ligand (with retinoid X receptor (RXR). The RXR-VDR heterodimer in contrast to other members...VDR-mediated transactivation by liganded RXR-VDR has not been fully characterized...unique facet of the intermolecular RXR-VDR interaction, where RXR actively participates...)

VDR TR3 similarities

Thyroid hormones and muscle differentiation

Decreased Retinoid X Receptor-{alpha} Protein Expression in Basal Cells Occurs in the Early Stage of Human Prostate Cancer Development 2004

Peroxisome Proliferator-Activated Receptor -β/δ, -γ Agonists and ResveratrolModulate Hypoxia Induced Changes in Nuclear Receptor Activators ofMuscle OxidativeMetabolism 2010

Polyclonal anti-RXR{alpha} (D-20) sc-553 ({Delta}N 197), anti-RXRß (C-20), anti-RXR{gamma} (Y-20), and anti-p34 cdc2 kinase (H-297) antibodies and polyclonal anti-phospho p44/p42 MAPK (ERK1/ERK2) antibody were from Santa Cruz Biotechnology, Inc. (Santa Cruz Biotechnology, CA) and Cell Signaling Technology (Beverly, MA), respectively.

DEFINITION

A short protein description with the molecular wheight, isoforms, etc...
Use, when available, the link to Wikipedia (Es Trypsin)

External links not available on Wikipedia have to be added here

THE GENE

DatabaseLink
WikigenesACADM
GeneCards"URL":
Your Favorite Gene Sigma"URL":

CHEMICAL STRUCTURE AND IMAGES

When relevant for the function

  • Primary structure
  • Secondary structure
  • Tertiary structure
  • Quaternary structure

Protein Aminoacids Percentage (Width 700 px)

SYNTHESIS AND TURNOVER

mRNA synthesis
protein synthesis

post-translational modifications
degradation

CELLULAR FUNCTIONS

cellular localization,

Nuclear import

Retinoid X Receptor Dominates the Nuclear Import and Export of the Unliganded Vitamin D Receptor, 2002

  • Liganded and unliganded vitamin D receptors (VDRs) carry out distinct functions; both types of functions require heterodimerization with retinoid X receptors (RXRs). Our recent studies with fluorescent protein chimeras of VDR and RXR, termed GFP-VDR, YFP-RXR, and RXR-BFP, indicated that RXR regulates VDR functions in part by regulating subcellular localization. Here we explored the mechanisms of this regulation. Photobleaching experiments demonstrated that YFP-RXR and both unliganded and liganded GFP-VDR shuttle constantly between nucleus and cytoplasm. To characterize RXR import, we identified a nuclear localization sequence (NLS) in the DNA-binding domain. Mutations in this NLS caused predominant cytoplasmic localization of nlsYFP-RXR and prevented transcriptional activity. The nlsRXR-BFP retained unliganded GFP-VDR in the cytoplasm and reduced baseline transcriptional activity. After calcitriol exposure, however, both GFP-VDR and nlsRXR-BFP entered the nucleus. We characterized receptor export rates and mechanisms using permeabilization experiments. Mutations in the calreticulin binding region slowed both GFP-VDR and YFP-RXR export. Coexpression of RXR-BFP slowed the export of unliganded GFP-VDR, whereas calcitriol treatment tripled the rate of GFP-VDR export. Treatment with leptomycin B, an inhibitor of CRM-1 receptor-mediated export, inhibited export of unliganded GFP-VDR but did not influence export of liganded GFP-VDR or YFP-RXR. Leptomycin B added before calcitriol similarly decreased hormone-induced luciferase activity but was ineffective when added subsequent to calcitriol. These results indicate that the unliganded and liganded VDR interact differently with the import and export receptors and with RXR. Most likely, the regulation of VDR nuclear import by RXR is essential for ligand-independent functions.
  • intracellular

biological function

Transcription Factors

Signalling through nuclear receptors, 2002

  • homodimers??
  • heterodimers
    • Liganded
    • Unliganded

Competition for RXR

As all these factors are active as heterodimers with RXR, RXR availability can became a limiting factor for hormones activity.

RXR scarcity can derive from:

  1. absolute lack of RXR (diet poor in proteins??)
  2. relative lack due to sequestration of RXR by an increased number of a specific liganded receptor (TR, VDR; RAR etc)
DatabaseLink
BRENDA - The Comprehensive Enzyme Information System"URL":
KEGG Pathways"URL":
Human Metabolome Database"URL":

REGULATION

DIAGNOSTIC USE

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