RAR-related orphan receptor alpha

RAR-related orphan receptor alpha (RORα), also known as NR1F1 (nuclear receptor subfamily 1, group F, member 1) is a is_associated_with::nuclear receptor that in humans is encoded by the RORA is_associated_with::gene. RORα participates in the transcriptional regulation of some genes involved in is_associated_with::circadian rhythm.

Discovery
The first three human isoforms of RORα were initially cloned and characterized as nuclear receptors in 1994 by Giguère and colleagues, when their structure and function were first studied.

In the early 2000s, various studies demonstrated that RORα displays rhythmic patterns of expression in a circadian cycle in the is_associated_with::liver, is_associated_with::kidney, is_associated_with::retina, and is_associated_with::lung. Of interest, it was around this time that RORα abundance was found to be circadian in the mammalian is_associated_with::suprachiasmatic nucleus. RORα is necessary for normal is_associated_with::circadian rhythms in mice, demonstrating its importance in is_associated_with::chronobiology.

Structure
The protein encoded by this gene is a member of the NR1 subfamily of nuclear hormone receptors. In humans, 4 isoforms of RORα have been identified, which are generated via alternative splicing and promoter usage, and exhibit differential tissue-specific expression. The is_associated_with::protein structure of RORα consists of four canonical functional groups: an is_associated_with::N-terminal (A/B) domain, a is_associated_with::DNA-binding domain containing two is_associated_with::zinc fingers, a hinge domain, and a C-terminal is_associated_with::ligand-binding domain. Within the ROR family, the DNA-binding domain is highly conserved, and the ligand-binding domain is only moderately conserved. Different isoforms of RORα have different binding specificities and strengths of transcriptional activity.

Regulation of circadian rhythm
The core is_associated_with::mammalian circadian clock is a is_associated_with::negative feedback loop which consists of Per1/Per2, Cry1/Cry2, Bmal1, and Clock. This feedback loop is stabilized through another loop involving the transcriptional regulation of Bmal1. is_associated_with::Transactivation of Bmal1 is regulated through the upstream ROR/REV-ERB Response Element (RRE) in the Bmal1 promoter, to which RORα and REV-ERBα bind. This stabilizing regulatory loop itself is induced by the Bmal1/Clock heterodimer, which induces transcription of RORα and REV-ERBα. RORα, which activates transcription of Bmal1, and REV-ERBα, which represses transcription of Bmal1, compete to bind to the RRE. This feedback loop regulating the expression of Bmal1 is thought to stabilize the core clock mechanism, helping to buffer it against changes in the environment.

Mechanism
Specific association with ROR elements (RORE) in regulatory regions is necessary for RORα’s function as a transcriptional activator. RORα achieves this by specific binding to a consensus core motif in RORE, RGGTCA. This interaction is possible through the association of RORα’s first zinc finger with the core motif in the major groove, the P-box, and the association of its C-terminal extension with the AT-rich region in the 5’ region of RORE.

Homology
RORα, RORβ, and RORγ are all transcriptional activators recognizing ROR-response elements. ROR-alpha is expressed in a variety of cell types and is involved in regulating several aspects of development, inflammatory responses, and is_associated_with::lymphocyte development. The RORα isoforms (RORα1 through RORα3) arise via alternative RNA processing, with RORα2 and RORα3 sharing an amino-terminal region different from RORα1. In contrast to RORα, RORβ is expressed in is_associated_with::Central Nervous System (CNS) tissues involved in processing sensory information and in generating is_associated_with::circadian rhythms while RORγ is critical in is_associated_with::lymph node is_associated_with::organogenesis and thymopoeisis.

The DNA-binding domains of the DHR3 orphan receptor in Drosophila shows especially close homology within is_associated_with::amino and is_associated_with::carboxy regions adjacent to the second zinc finger region in RORα, suggesting that this group of residues is important for the proteins' functionalities.

PDP1 and VRI in Drosophila regulate circadian rhythm's by competing for the same binding site, the VP box, similarly to how ROR and REV-ERB competitively bind to RRE. PDP1 and VRI constitute a is_associated_with::feedback loop and are functional homologs of ROR and REV-ERB in mammals.

Direct orthologs of this gene have been identified in mice and humans.

Human is_associated_with::cytochrome c pseudogene HC2 and RORα share overlapping genomic organization with the HC2 pseudogene located within the RORα2 transcription unit. The nucleotide and deduced amino acid sequences of cytochrome c-processed pseudogene are on the sense strand while those of the RORα2 amino-terminal exon are on the antisense strand.

Interactions

 * DNA: RORα binds to the P-box of the RORE.
 * is_associated_with::Co-activators:
 * is_associated_with::SRC-1, CBP, p300, TRIP-l, TRIP-230, transcription intermediary protein-1 (TIF-1), peroxisome proliferator-binding protein (PBP), and GRIP-1 physically interact with RORα.
 * LXXLL motif: ROR interacts with SRC-1, GRIP-l, CBP, and p300 via the LXXLL (L=Leucine, X=any amino acid) motifs on these proteins.
 * is_associated_with::Ubiquitination: RORα is targeted for the is_associated_with::proteasome by ubiquitination. A co-repressor, Hairless, stabilizes RORα by protecting it from this process, which also represses RORα.
 * Sumoylation: UBE21/UBC9: Ubiquitin-conjugating enzyme I interacts with RORs, but its effect is not yet known.
 * is_associated_with::Phosphorylation:
 * Phosphorylation of RORα1, which inhibits its transcriptional activity, is induced by is_associated_with::Protein Kinase C.
 * ERK2: is_associated_with::Extracellular signal-regulated kinase-2 also phosphorylates RORα.
 * ATXN1: ATXN1 and RORα form part of a protein complex in is_associated_with::Purkinje cells.
 * is_associated_with::FOXP3: FOXP3 directly represses the transcriptional activity of RORs.
 * is_associated_with::NME1: ROR has been shown to specifically interact with NME1.
 * NM23-2: NM23-2 is a nucleoside diphosphate is_associated_with::kinase involved in organogenesis and differentiation.
 * NM23-1: NM23-1 is the product of a tumor is_associated_with::metastasis suppressor candidate gene.

As a drug target
Because RORα and REV-ERBα are nuclear receptors that share the same target genes and are involved in processes that regulate is_associated_with::metabolism, development, immunity, and circadian rhythm, they show potential as drug targets. Synthetic ligands have a variety of potential therapeutic uses, and can be used to treat diseases such as is_associated_with::diabetes, is_associated_with::atherosclerosis, is_associated_with::autoimmunity, and is_associated_with::cancer. T0901317 and SR1001, two synthetic ligands, have been found to be RORα and RORγ inverse is_associated_with::agonists that suppress reporter activity and have been shown to delay onset and clinical severity of is_associated_with::multiple sclerosis and other is_associated_with::Th17 cell-mediated autoimmune diseases. SR1078 has been discovered as a RORα and RORγ agonist that increases the expression of G6PC and FGF21, yielding the therapeutic potential to treat is_associated_with::obesity and diabetes as well as cancer of the is_associated_with::breast, is_associated_with::ovaries, and is_associated_with::prostate. SR3335 has also been discovered as a RORα inverse agonist.