| Tchem | Nuclear receptor ROR-alpha |
Nuclear receptor that binds DNA as a monomer to ROR response elements (RORE) containing a single core motif half-site 5'-AGGTCA-3' preceded by a short A-T-rich sequence. Key regulator of embryonic development, cellular differentiation, immunity, circadian rhythm as well as lipid, steroid, xenobiotics and glucose metabolism. Considered to have intrinsic transcriptional activity, have some natural ligands like oxysterols that act as agonists (25-hydroxycholesterol) or inverse agonists (7-oxygenated sterols), enhancing or repressing the transcriptional activity, respectively. Recruits distinct combinations of cofactors to target genes regulatory regions to modulate their transcriptional expression, depending on the tissue, time and promoter contexts. Regulates genes involved in photoreceptor development including OPN1SW, OPN1SM and ARR3 and skeletal muscle development with MYOD1. Required for proper cerebellum development, regulates SHH gene expression, among others, to induce granule cells proliferation as well as expression of genes involved in calcium-mediated signal transduction. Regulates the circadian expression of several clock genes, including CLOCK, ARNTL/BMAL1, NPAS2 and CRY1. Competes with NR1D1 for binding to their shared DNA response element on some clock genes such as ARNTL/BMAL1, CRY1 and NR1D1 itself, resulting in NR1D1-mediated repression or RORA-mediated activation of clock genes expression, leading to the circadian pattern of clock genes expression. Therefore influences the period length and stability of the clock. Regulates genes involved in lipid metabolism such as apolipoproteins APOA1, APOA5, APOC3 and PPARG. In liver, has specific and redundant functions with RORC as positive or negative modulator of expression of genes encoding phase I and phase II proteins involved in the metabolism of lipids, steroids and xenobiotics, such as CYP7B1 and SULT2A1. Induces a rhythmic expression of some of these genes. In addition, interplays functionally with NR1H2 and NR1H3 for the regulation of genes involved in cholesterol metabolism. Also involved in the regulation of hepatic glucose metabolism through the modulation of G6PC and PCK1. In adipose tissue, plays a role as negative regulator of adipocyte differentiation, probably acting through dual mechanisms. May suppress CEBPB-dependent adipogenesis through direct interaction and PPARG-dependent adipogenesis through competition for DNA-binding. Downstream of IL6 and TGFB and synergistically with RORC isoform 2, is implicated in the lineage specification of uncommitted CD4(+) T-helper (T(H)) cells into T(H)17 cells, antagonizing the T(H)1 program. Probably regulates IL17 and IL17F expression on T(H) by binding to the essential enhancer conserved non-coding sequence 2 (CNS2) in the IL17-IL17F locus. Involved in hypoxia signaling by interacting with and activating the transcriptional activity of HIF1A. May inhibit cell growth in response to cellular stress. May exert an anti-inflammatory role by inducing CHUK expression and inhibiting NF-kappa-B signaling.
The protein encoded by this gene is a member of the NR1 subfamily of nuclear hormone receptors. It can bind as a monomer or as a homodimer to hormone response elements upstream of several genes to enhance the expression of those genes. The encoded protein has been shown to interact with NM23-2, a nucleoside diphosphate kinase involved in organogenesis and differentiation, as well as with NM23-1, the product of a tumor metastasis suppressor candidate gene. Also, it has been shown to aid in the transcriptional regulation of some genes involved in circadian rhythm. Four transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Feb 2014]
The protein encoded by this gene is a member of the NR1 subfamily of nuclear hormone receptors. It can bind as a monomer or as a homodimer to hormone response elements upstream of several genes to enhance the expression of those genes. The encoded protein has been shown to interact with NM23-2, a nucleoside diphosphate kinase involved in organogenesis and differentiation, as well as with NM23-1, the product of a tumor metastasis suppressor candidate gene. Also, it has been shown to aid in the transcriptional regulation of some genes involved in circadian rhythm. Four transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Feb 2014]
Comments
| Disease | Target Count |
|---|---|
| Autistic Disorder | 320 |
| Peripheral Neuropathy | 303 |
| Stomach Neoplasms | 282 |
| Disease | Target Count | Z-score | Confidence |
|---|---|---|---|
| Acquired metabolic disease | 267 | 0.0 | 1.0 |
| Alzheimer's disease | 644 | 0.0 | 1.0 |
| Asthma | 349 | 0.0 | 2.0 |
| Mental depression | 58 | 0.0 | 1.0 |
| Schizophrenia | 503 | 0.0 | 1.0 |
| Disease | Target Count | Z-score | Confidence |
|---|---|---|---|
| Lown-Ganong-Levine syndrome | 3 | 4.213 | 2.1 |
| Bipolar Disorder | 266 | 3.19 | 1.6 |
| Seasonal affective disorder | 25 | 3.104 | 1.6 |
| Species | Source |
|---|---|
| Chimp | OMA EggNOG |
| Macaque | OMA EggNOG Inparanoid |
| Mouse | OMA EggNOG Inparanoid |
| Dog | OMA EggNOG Inparanoid |
| Cow | OMA EggNOG Inparanoid |
| Pig | OMA EggNOG |
| Opossum | EggNOG Inparanoid |
| Platypus | OMA EggNOG Inparanoid |
| Chicken | OMA EggNOG Inparanoid |
| Anole lizard | OMA EggNOG Inparanoid |
| Xenopus | OMA EggNOG Inparanoid |
CHEMBL3617295
pEC50 7.07
CHEMBL3314003
pEC50 7.54
CHEMBL497834
pKi 7.92
CHEMBL497207
pKi 7.92
CHEMBL1278177
pKi 7.92
| AID | Type | Active / Inconclusive / Inactive | Description |
|---|---|---|---|
| 2139 | summary |
2 / 0 / 0 | Summary of probe development efforts to identify novel modulators of the Retinoic acid receptor-related Orphan Receptors (ROR). |
| 2277 | screening |
14 / 0 / 0 | Center Based Initiative to identify novel modulators of the Retinoic acid receptor-related Orphan Receptors (ROR): luminescence-based high throughput cell-based assay to identify modulators of human nuclear receptors. |
| 463078 | other |
1 / 0 / 5 | Late stage assay provider results from the probe development effort to identify selective inverse agonists of the Retinoic acid receptor-related Orphan Receptors (RORA): luminescent-based assay to identify RORA inhibitors |
| 463152 | confirmatory |
1 / 0 / 0 | Late stage assay provider results from the probe development effort to identify selective inverse agonists of the Retinoic acid receptor-related Orphan Receptors (RORA): luminescence-based dose response assay to identify RORA inhibitors |
| 504906 | other |
1 / 0 / 0 | Late stage assay provider results from the probe development effort to identify selective inverse agonists of the Retinoic acid receptor-related Orphan Receptors (RORA): radioligand binding assay for RORa using [3H]25-hydroxycholesterol to determine whether probe candidates bind directly to RORa |
| 504934 | other |
1 / 0 / 0 | Late stage assay provider results from the probe development effort to identify inverse agonists of the liver receptor homolog-1 (LRH-1; NR5A2): luminescence-based high throughput cell-based assay to identify modulators of human nuclear receptors |
| 624277 | other |
1 / 0 / 0 | Late stage assay provider counterscreen from the probe development effort to identify selective inverse agonists of the Retinoic acid receptor-related Orphan Receptor Gamma (RORC): Luminescence-based cell-based assays using RORE-Luc, IL-17-Luc, and ABCA1-Luc Reporters |
| 624279 | confirmatory |
1 / 0 / 0 | Late stage assay provider counterscreen from the probe development effort to identify selective inverse agonists of the Retinoic acid receptor-related Orphan Receptor Gamma (RORC): luminescence-based cell-based dose response panel assay against ROR alpha, ROR gamma, LXR, FXR, and VP16 |
| PMID | Text |
|---|---|
| 26731717 | status epilepticus induced by pilocarpine is able to change the expression and daily variation of RORalpha in the rat hippocampal area during the acute and silent phases |
| 26515929 | A common SNP in the RORA gene (rs2899663) was associated with a 21% reduced odds of placental abruption. |
| 26184991 | In a Han Chinese population, an association between RORA gene variation and depression personality trait was found. |
| 25953430 | Identify RORalpha as being essential to drive inflammation in experimental epidermolysis bullosa acquisita. |
| 25892098 | The RORA intronic SNP rs11632098 was associated with greater odds of reporting depressive symptoms in older adults. |
| 25826113 | Retinoid-related orphan receptor alpha has gained attention as a new candidate in stress-related disorders, especially depression. |
| 25789810 | associations between NR1D1, RORA and RORB genes and bipolar disorder.( |
| 25668517 | RORA rs12912233 alone might be a possible risk variant for epilepsy in Malaysian Chinese, but that, together with RORA rs880626 and SCN1A rs3812718, this polymorphism may have a synergistic effect in the epilepsy risk in Malaysians. |
| 25500738 | RORalpha and its target gene expressions are lower in colorectal tumor tissue compared with control colorectal tissue. |
| 25362032 | the data presented in this report are that RORA is linked in important ways to molecules that could be playing important roles in the AD etiology. |
| More... |
MESAPAAPDPAASEPGSSGADAAAGSRETPLNQESARKSEPPAPVRRQSYSSTSRGISVTKKTHTSQIEI 1 - 70 IPCKICGDKSSGIHYGVITCEGCKGFFRRSQQSNATYSCPRQKNCLIDRTSRNRCQHCRLQKCLAVGMSR 71 - 140 DAVKFGRMSKKQRDSLYAEVQKHRMQQQQRDHQQQPGEAEPLTPTYNISANGLTELHDDLSNYIDGHTPE 141 - 210 GSKADSAVSSFYLDIQPSPDQSGLDINGIKPEPICDYTPASGFFPYCSFTNGETSPTVSMAELEHLAQNI 211 - 280 SKSHLETCQYLREELQQITWQTFLQEEIENYQNKQREVMWQLCAIKITEAIQYVVEFAKRIDGFMELCQN 281 - 350 DQIVLLKAGSLEVVFIRMCRAFDSQNNTVYFDGKYASPDVFKSLGCEDFISFVFEFGKSLCSMHLTEDEI 351 - 420 ALFSAFVLMSADRSWLQEKVKIEKLQQKIQLALQHVLQKNHREDGILTKLICKVSTLRALCGRHTEKLMA 421 - 490 FKAIYPDIVRLHFPPLYKELFTSEFEPAMQIDG 491 - 523 //
| PMID | Year | Title |
|---|---|---|
| 26731717 | 2016 | Pilocarpine-induced epilepsy alters the expression and daily variation of the nuclear receptor ROR? in the hippocampus of rats. |
| 26515929 | 2015 | Circadian clock-related genetic risk scores and risk of placental abruption. |
| 26184991 | 2015 | Retinoid-related orphan receptor alpha (RORA) gene variation is associated with trait depression. |
| 25953430 | 2015 | The retinoid-related orphan receptor alpha is essential for the end-stage effector phase of experimental epidermolysis bullosa acquisita. |
| 25892098 | 2015 | Associations of PER3 and RORA Circadian Gene Polymorphisms and Depressive Symptoms in Older Adults. |
| 25826113 | 2015 | RNA expression profiling in depressed patients suggests retinoid-related orphan receptor alpha as a biomarker for antidepressant response. |
| 25789810 | 2015 | Investigation of associations between NR1D1, RORA and RORB genes and bipolar disorder. |
| 25668517 | 2015 | RORA gene rs12912233 and rs880626 polymorphisms and their interaction with SCN1A rs3812718 in the risk of epilepsy: a case-control study in Malaysia. |
| 25500738 | 2015 | ROR? inhibits adipocyte-conditioned medium-induced colorectal cancer cell proliferation and migration and chick embryo chorioallantoic membrane angiopoiesis. |
| 25416956 | 2014 | A proteome-scale map of the human interactome network. |
| More... |
