RAR-alfa

RAR-alfa
Dostupne strukture PDB Pretraga ortologa: PDBe RCSB Spisak PDB ID kodova 1DKF, 1DSZ, 3A9E, 3KMR, 3KMZ, 4DQM, 5K13
Identifikatori
Aliasi	RARA
Vanjski ID-jevi	OMIM: 180240 MGI: 97856 HomoloGene: 20262 GeneCards: RARA
Lokacija gena (čovjek) Hrom. Hromosom 17 (čovjek)[1] Bend 17q21.2 Početak 40,309,180 bp[1] Kraj 40,357,643 bp[1]
Lokacija gena (miš) Hrom. Hromosom 11 (miš)[2] Bend 11 D|11 62.76 cM Početak 98,818,644 bp[2] Kraj 98,865,768 bp[2]
Obrazac RNK ekspresije Više referentnih podataka o ekspresiji
Ontologija gena Molekularna funkcija • retinoic acid binding • GO:0001106 transcription corepressor activity • protein domain specific binding • GO:0001131, GO:0001151, GO:0001130, GO:0001204 DNA-binding transcription factor activity • GO:0038050, GO:0004886, GO:0038051 nuclear receptor activity • mRNA 5'-UTR binding • signaling receptor binding • RNA polymerase II transcription regulatory region sequence-specific DNA binding • retinoic acid-responsive element binding • transcription factor binding • vezivanje iona metala • steroid hormone receptor activity • vezivanje enzima • vezivanje iona cinka • GO:0001948, GO:0016582 vezivanje za proteine • vezivanje sa DNK • sequence-specific DNA binding • GO:0001105 transcription coactivator activity • protein kinase A binding • protein kinase B binding • translation repressor activity, mRNA regulatory element binding • alpha-actinin binding • protein heterodimerization activity • chromatin DNA binding • GO:0001200, GO:0001133, GO:0001201 DNA-binding transcription factor activity, RNA polymerase II-specific • histone deacetylase binding • GO:0000975 transcription cis-regulatory region binding • nuclear receptor coactivator activity • signaling receptor activity Ćelijska komponenta • citoplazma • actin cytoskeleton • perinuklearno područje citoplazme • neuron projection • jedro • cell surface • nukleoplazma • soma • dendrit • citosol • RNA polymerase II transcription regulator complex Biološki proces • growth plate cartilage development • germ cell development • cellular response to retinoic acid • ureteric bud development • positive regulation of interleukin-5 production • prostate gland development • limb development • apoptotic cell clearance • chondroblast differentiation • regulation of granulocyte differentiation • protein phosphorylation • response to vitamin A • face development • Spermatogeneza • response to ethanol • negative regulation of cell population proliferation • steroid hormone mediated signaling pathway • regulation of apoptotic process • response to cytokine • negative regulation of translation • GO:0009373 regulation of transcription, DNA-templated • negative regulation of cell differentiation • negative regulation of gene expression • transcription, DNA-templated • cellular response to estrogen stimulus • GO:0060469, GO:0009371 positive regulation of transcription, DNA-templated • positive regulation of cell cycle • regulation of myelination • positive regulation of neuron differentiation • negative regulation of tumor necrosis factor production • transcription initiation from RNA polymerase II promoter • trachea cartilage development • glandular epithelial cell development • male gonad development • negative regulation of cartilage development • response to retinoic acid • negative regulation of granulocyte differentiation • multicellular organism growth • female pregnancy • negative regulation of apoptotic process • GO:1901227 negative regulation of transcription by RNA polymerase II • positive regulation of interleukin-4 production • regulation of synaptic plasticity • outflow tract septum morphogenesis • GO:0045996 negative regulation of transcription, DNA-templated • negative regulation of interferon-gamma production • response to estradiol • negative regulation of translational initiation • embryonic camera-type eye development • positive regulation of interleukin-13 production • neural tube closure • positive regulation of binding • retinoic acid receptor signaling pathway • GO:1901313 positive regulation of gene expression • Sertoli cell fate commitment • positive regulation of cell population proliferation • positive regulation of T-helper 2 cell differentiation • ventricular cardiac muscle cell differentiation • liver development • cellular response to lipopolysaccharide • bone development • hippocampus development • GO:0072468 Transdukcija signala • GO:0003257, GO:0010735, GO:1901228, GO:1900622, GO:1904488 positive regulation of transcription by RNA polymerase II • multicellular organism development • hormone-mediated signaling pathway • Ćelijska diferencijacija • response to lipid • gland development • bone morphogenesis • epithelium development Izvori:Amigo / QuickGO
Ortolozi
Vrste	Čovjek	Miš
Entrez	5914	19401
Ensembl	ENSG00000131759	ENSMUSG00000037992
UniProt	P10276 Q6I9R7	P11416
RefSeq (mRNK)	NM_000964 NM_001024809 NM_001033603 NM_001145301 NM_001145302	NM_001176528 NM_001177302 NM_001177303 NM_009024 NM_001361954
RefSeq (bjelančevina)	NP_000955 NP_001019980 NP_001138773 NP_001138774 NP_000955.1 NP_001138773.1	NP_001169999 NP_001170773 NP_001170774 NP_033050 NP_001348883
Lokacija (UCSC)	Chr 17: 40.31 – 40.36 Mb	Chr 11: 98.82 – 98.87 Mb
PubMed pretraga	[3]	[4]
Wikipodaci
Pogledaj/uredi – čovjek Pogledaj/uredi – miš

Receptor alfa retinojske kiseline (RAR-α), znan i kao NR1B1 (član 1 grupe B potporodice 1 jedarnih receptora) jest jedarni receptorski protein koji je kod ljudi kodiran genom RARA sa hromosoma 17.^[5][6]

NR1B1 je gen sa proteinskim proizvodom i ima hromosomsku lokaciju 17q21.2. RARA kodira receptora jedarnog hormona, receptor retinojske kiseline, podtip alfa i sam je transkripcijski faktor. Postoje još dva podtipa RAR-a, beta i gama.^[7][8]

Aminokiselinska sekvenca

Dužina polipeptidnog lanca je 462 aminokiseline, a molekulska težina 50.771 Da.

• C: Cistein
• D: Asparaginska kiselina
• E: Glutaminska kiselina
• F: Fenilalanin
• G: Glicin
• H: Histidin
• I: Izoleucin
• K: Lizin
• L: Leucin
• M: Metionin
• N: Asparagin
• P: Prolin
• Q: Glutamin
• R: Arginin
• S: Serin
• T: Treonin
• V: Valin
• W: Triptofan
• Y: Tirozin

10		20		30		40		50
MASNSSSCPT		PGGGHLNGYP		VPPYAFFFPP		MLGGLSPPGA		LTTLQHQLPV
SGYSTPSPAT		IETQSSSSEE		IVPSPPSPPP		LPRIYKPCFV		CQDKSSGYHY
GVSACEGCKG		FFRRSIQKNM		VYTCHRDKNC		IINKVTRNRC		QYCRLQKCFE
VGMSKESVRN		DRNKKKKEVP		KPECSESYTL		TPEVGELIEK		VRKAHQETFP
ALCQLGKYTT		NNSSEQRVSL		DIDLWDKFSE		LSTKCIIKTV		EFAKQLPGFT
TLTIADQITL		LKAACLDILI		LRICTRYTPE		QDTMTFSDGL		TLNRTQMHNA
GFGPLTDLVF		AFANQLLPLE		MDDAETGLLS		AICLICGDRQ		DLEQPDRVDM
LQEPLLEALK		VYVRKRRPSR		PHMFPKMLMK		ITDLRSISAK		GAERVITLKM
EIPGSMPPLI		QEMLENSEGL		DTLSGQPGGG		GRDGGGLAPP		PGSCSPSLSP
SSNRSSPATH		SP

Funkcija

Retinoidnu signalizaciju transduciraju članovi dvije porodice jedarnih receptora, receptor retinojske kiseline (RAR) i retinoidnui X-receptor (RXR), koji formiraju RXR/RAR heterodimere. U nedostatku liganda, DNK vezani RXR/RARA potiskuje transkripciju, regrutacijom korepresora NCOR1, SMRT (NCOR2), i histon-deacetilaze. Kada se ligand veže za kompleks, inducira konformacijsku promjenu koja omogućava regrutovanje koaktivatora, histon-acetiltransferaza i osnovnog transkripcijskog mehanizma.^[9]

Receptor retinoične kiseline alfa, protein, stupa u interakciju sa retinojskom kiselinom, derivatom vitamina A, koji ima važnu ulogu u rastu ćelija, diferencijaciji i formiranju organa u razvoju embriona.^[8][10]

Kada se retinoična kiselina veže za RAR, oni pokreću transkripciju i omogućavaju ekspresiju njihovog gena.^[10]

Klinički značaj

RA signalizacija je u korelacijama sa nekoliko signalnih puteva u ranom embrionskom razvoju. Prvo, učestvuje u formiranju embrionske osovine, koja uspostavlja simetriju u potomstvu. RA također utiče na nervnu diferencijaciju. regulacijom ekspresije proneurvnog indukcionog faktora meurogenina 2 (neurog2). RA utiče na kardiogenezu, jer ima posebnu ulogu u formiranju srčane pretkomore. RA također ima ulogu u razvoju pankreasa, bubrega, pluća i ekstremiteta.^[10]

Translokacije koje uvijek uključuju preuređivanje gena RARA su kardinalna karakteristika akutne promijelocitne leukemije (APL; MIM 612376). Najčešća translokacija je t(15,17)(q21;q22), koja spaja gen RARA sa genom PML.^[11]

Interakcije

Pokazalo se da receptor alfa retinojske kiseline reaguje sa:

• BAG1,^[12]
• CLOCK,^[13]
• CCND3,^[14]
• NCOA6,^[15][16][17]
• NCOR1,^[18][19]
• NCOR2,^[20][21]
• NPAS2,^[13]
• NRIP1,^[22][23][24]
• NR0B2,^[25][26]
• NR4A2,^[27]
• PML^[28]
• RXRA.^[29][30]
• Src,^[31][32]
• TADA3L,^[33] i
• ZBTB16.^[34]

Genetic Studies

Knock-out mice studies showed that a deletion in one of the copies of the RARA gene did not create any observable defect, while deletion of both copies shoes symptoms similar to that of Vitamin A deficiency. This proved that all 3 subtypes of RARs work redundantly.

See also

• Retinoic acid receptor
• Retinoic X Receptor
• Acute promyelocytic leukemia

Reference

1. GRCh38: Ensembl release 89: ENSG00000131759 - Ensembl, maj 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000037992 - Ensembl, maj 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Giguere V, Ong ES, Segui P, Evans RM (1987). "Identification of a receptor for the morphogen retinoic acid". Nature. 330 (6149): 624–9. Bibcode:1987Natur.330..624G. doi:10.1038/330624a0. PMID 2825036. S2CID 4308015.
6. Anderson LA, Friedman L, Osborne-Lawrence S, Lynch E, Weissenbach J, Bowcock A, King MC (septembar 1993). "High-density genetic map of the BRCA1 region of chromosome 17q12-q21". Genomics. 17 (3): 618–23. doi:10.1006/geno.1993.1381. PMID 8244378.
7. "Gene symbol report | HUGO Gene Nomenclature Committee". www.genenames.org. Pristupljeno 27. 4. 2021.
8. "OMIM Entry - * 180240 - RETINOIC ACID RECEPTOR, ALPHA; RARA". www.omim.org. Pristupljeno 27. 4. 2021.
9. "Entrez Gene: retinoic acid receptor".
10. Kam RK, Deng Y, Chen Y, Zhao H (mart 2012). "Retinoic acid synthesis and functions in early embryonic development". Cell & Bioscience. 2 (1): 11. doi:10.1186/2045-3701-2-11. PMC 3325842. PMID 22439772.
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13. McNamara P, Seo SB, Rudic RD, Sehgal A, Chakravarti D, FitzGerald GA (juni 2001). "Regulation of CLOCK and MOP4 by nuclear hormone receptors in the vasculature: a humoral mechanism to reset a peripheral clock". Cell. 105 (7): 877–89. doi:10.1016/S0092-8674(01)00401-9. PMID 11439184. S2CID 6251321.
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15. Lee SK, Jung SY, Kim YS, Na SY, Lee YC, Lee JW (februar 2001). "Two distinct nuclear receptor-interaction domains and CREB-binding protein-dependent transactivation function of activating signal cointegrator-2". Molecular Endocrinology. 15 (2): 241–54. doi:10.1210/me.15.2.241. PMID 11158331.
16. Lee SK, Anzick SL, Choi JE, Bubendorf L, Guan XY, Jung YK, et al. (novembar 1999). "A nuclear factor, ASC-2, as a cancer-amplified transcriptional coactivator essential for ligand-dependent transactivation by nuclear receptors in vivo". The Journal of Biological Chemistry. 274 (48): 34283–93. doi:10.1074/jbc.274.48.34283. PMID 10567404.
17. Ko L, Cardona GR, Chin WW (maj 2000). "Thyroid hormone receptor-binding protein, an LXXLL motif-containing protein, functions as a general coactivator". Proceedings of the National Academy of Sciences of the United States of America. 97 (11): 6212–7. Bibcode:2000PNAS...97.6212K. doi:10.1073/pnas.97.11.6212. PMC 18584. PMID 10823961.
18. Dowell P, Ishmael JE, Avram D, Peterson VJ, Nevrivy DJ, Leid M (maj 1999). "Identification of nuclear receptor corepressor as a peroxisome proliferator-activated receptor alpha interacting protein". The Journal of Biological Chemistry. 274 (22): 15901–7. doi:10.1074/jbc.274.22.15901. PMID 10336495.
19. Guidez F, Ivins S, Zhu J, Söderström M, Waxman S, Zelent A (april 1998). "Reduced retinoic acid-sensitivities of nuclear receptor corepressor binding to PML- and PLZF-RARalpha underlie molecular pathogenesis and treatment of acute promyelocytic leukemia". Blood. 91 (8): 2634–42. doi:10.1182/blood.V91.8.2634.2634_2634_2642. PMID 9531570.
20. Dong S, Tweardy DJ (april 2002). "Interactions of STAT5b-RARalpha, a novel acute promyelocytic leukemia fusion protein, with retinoic acid receptor and STAT3 signaling pathways". Blood. 99 (8): 2637–46. doi:10.1182/blood.V99.8.2637. PMID 11929748.
21. Hong SH, David G, Wong CW, Dejean A, Privalsky ML (august 1997). "SMRT corepressor interacts with PLZF and with the PML-retinoic acid receptor alpha (RARalpha) and PLZF-RARalpha oncoproteins associated with acute promyelocytic leukemia". Proceedings of the National Academy of Sciences of the United States of America. 94 (17): 9028–33. Bibcode:1997PNAS...94.9028H. doi:10.1073/pnas.94.17.9028. PMC 23013. PMID 9256429.
22. Hu X, Chen Y, Farooqui M, Thomas MC, Chiang CM, Wei LN (januar 2004). "Suppressive effect of receptor-interacting protein 140 on coregulator binding to retinoic acid receptor complexes, histone-modifying enzyme activity, and gene activation". The Journal of Biological Chemistry. 279 (1): 319–25. doi:10.1074/jbc.M307621200. PMID 14581481.
23. Farooqui M, Franco PJ, Thompson J, Kagechika H, Chandraratna RA, Banaszak L, Wei LN (februar 2003). "Effects of retinoid ligands on RIP140: molecular interaction with retinoid receptors and biological activity". Biochemistry. 42 (4): 971–9. doi:10.1021/bi020497k. PMID 12549917.
24. L'Horset F, Dauvois S, Heery DM, Cavaillès V, Parker MG (novembar 1996). "RIP-140 interacts with multiple nuclear receptors by means of two distinct sites". Molecular and Cellular Biology. 16 (11): 6029–36. doi:10.1128/MCB.16.11.6029. PMC 231605. PMID 8887632.
25. Seol W, Choi HS, Moore DD (maj 1996). "An orphan nuclear hormone receptor that lacks a DNA binding domain and heterodimerizes with other receptors". Science. 272 (5266): 1336–9. Bibcode:1996Sci...272.1336S. doi:10.1126/science.272.5266.1336. PMID 8650544. S2CID 32853062.
26. Seol W, Hanstein B, Brown M, Moore DD (oktobar 1998). "Inhibition of estrogen receptor action by the orphan receptor SHP (short heterodimer partner)". Molecular Endocrinology. 12 (10): 1551–7. doi:10.1210/me.12.10.1551. PMID 9773978.
27. Perlmann T, Jansson L (april 1995). "A novel pathway for vitamin A signaling mediated by RXR heterodimerization with NGFI-B and NURR1". Genes & Development. 9 (7): 769–82. doi:10.1101/gad.9.7.769. PMID 7705655.
28. Zhong S, Delva L, Rachez C, Cenciarelli C, Gandini D, Zhang H, et al. (novembar 1999). "A RA-dependent, tumour-growth suppressive transcription complex is the target of the PML-RARalpha and T18 oncoproteins". Nature Genetics. 23 (3): 287–95. doi:10.1038/15463. PMID 10610177. S2CID 23613492.
29. Benkoussa M, Brand C, Delmotte MH, Formstecher P, Lefebvre P (juli 2002). "Retinoic acid receptors inhibit AP1 activation by regulating extracellular signal-regulated kinase and CBP recruitment to an AP1-responsive promoter". Molecular and Cellular Biology. 22 (13): 4522–34. doi:10.1128/MCB.22.13.4522-4534.2002. PMC 133906. PMID 12052862.
30. Bugge TH, Pohl J, Lonnoy O, Stunnenberg HG (april 1992). "RXR alpha, a promiscuous partner of retinoic acid and thyroid hormone receptors". The EMBO Journal. 11 (4): 1409–18. doi:10.1002/j.1460-2075.1992.tb05186.x. PMC 556590. PMID 1314167.
31. Kim HJ, Yi JY, Sung HS, Moore DD, Jhun BH, Lee YC, Lee JW (septembar 1999). "Activating signal cointegrator 1, a novel transcription coactivator of nuclear receptors, and its cytosolic localization under conditions of serum deprivation". Molecular and Cellular Biology. 19 (9): 6323–32. doi:10.1128/mcb.19.9.6323. PMC 84603. PMID 10454579.
32. He B, Wilson EM (mart 2003). "Electrostatic modulation in steroid receptor recruitment of LXXLL and FXXLF motifs". Molecular and Cellular Biology. 23 (6): 2135–50. doi:10.1128/MCB.23.6.2135-2150.2003. PMC 149467. PMID 12612084.
33. Zeng M, Kumar A, Meng G, Gao Q, Dimri G, Wazer D, et al. (novembar 2002). "Human papilloma virus 16 E6 oncoprotein inhibits retinoic X receptor-mediated transactivation by targeting human ADA3 coactivator". The Journal of Biological Chemistry. 277 (47): 45611–8. doi:10.1074/jbc.M208447200. PMID 12235159.
34. Martin PJ, Delmotte MH, Formstecher P, Lefebvre P (septembar 2003). "PLZF is a negative regulator of retinoic acid receptor transcriptional activity". Nuclear Receptor. 1 (1): 6. doi:10.1186/1478-1336-1-6. PMC 212040. PMID 14521715.

Dopunska literatura

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• Sirulnik A, Melnick A, Zelent A, Licht JD (septembar 2003). "Molecular pathogenesis of acute promyelocytic leukaemia and APL variants". Best Practice & Research. Clinical Haematology. 16 (3): 387–408. doi:10.1016/S1521-6926(03)00062-8. PMID 12935958.
• Kliewer SA, Umesono K, Mangelsdorf DJ, Evans RM (januar 1992). "Retinoid X receptor interacts with nuclear receptors in retinoic acid, thyroid hormone and vitamin D3 signalling". Nature. 355 (6359): 446–9. Bibcode:1992Natur.355..446K. doi:10.1038/355446a0. PMC 6159885. PMID 1310351.
• Kastner P, Perez A, Lutz Y, Rochette-Egly C, Gaub MP, Durand B, et al. (februar 1992). "Structure, localization and transcriptional properties of two classes of retinoic acid receptor alpha fusion proteins in acute promyelocytic leukemia (APL): structural similarities with a new family of oncoproteins". The EMBO Journal. 11 (2): 629–42. doi:10.1002/j.1460-2075.1992.tb05095.x. PMC 556495. PMID 1311253.
• Baniahmad A, Köhne AC, Renkawitz R (mart 1992). "A transferable silencing domain is present in the thyroid hormone receptor, in the v-erbA oncogene product and in the retinoic acid receptor". The EMBO Journal. 11 (3): 1015–23. doi:10.1002/j.1460-2075.1992.tb05140.x. PMC 556542. PMID 1347744.
• de Thé H, Lavau C, Marchio A, Chomienne C, Degos L, Dejean A (august 1991). "The PML-RAR alpha fusion mRNA generated by the t(15;17) translocation in acute promyelocytic leukemia encodes a functionally altered RAR". Cell. 66 (4): 675–84. doi:10.1016/0092-8674(91)90113-D. PMID 1652369. S2CID 40272758.
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• Brand NJ, Petkovich M, Chambon P (decembar 1990). "Characterization of a functional promoter for the human retinoic acid receptor-alpha (hRAR-alpha)". Nucleic Acids Research. 18 (23): 6799–806. doi:10.1093/nar/18.23.6799. PMC 332734. PMID 2175878.
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• Chen Z, Guidez F, Rousselot P, Agadir A, Chen SJ, Wang ZY, et al. (februar 1994). "PLZF-RAR alpha fusion proteins generated from the variant t(11;17)(q23;q21) translocation in acute promyelocytic leukemia inhibit ligand-dependent transactivation of wild-type retinoic acid receptors". Proceedings of the National Academy of Sciences of the United States of America. 91 (3): 1178–82. Bibcode:1994PNAS...91.1178C. doi:10.1073/pnas.91.3.1178. PMC 521477. PMID 8302850.
• Redner RL, Rush EA, Faas S, Rudert WA, Corey SJ (februar 1996). "The t(5;17) variant of acute promyelocytic leukemia expresses a nucleophosmin-retinoic acid receptor fusion". Blood. 87 (3): 882–6. doi:10.1182/blood.V87.3.882.bloodjournal873882. PMID 8562957.
• Kamei Y, Xu L, Heinzel T, Torchia J, Kurokawa R, Gloss B, et al. (maj 1996). "A CBP integrator complex mediates transcriptional activation and AP-1 inhibition by nuclear receptors". Cell. 85 (3): 403–14. doi:10.1016/S0092-8674(00)81118-6. PMID 8616895. S2CID 16273727.
• Liu W, Hellman P, Li Q, Yu WR, Juhlin C, Nordlinder H, et al. (decembar 1996). "Biosynthesis and function of all-trans- and 9-cis-retinoic acid in parathyroid cells". Biochemical and Biophysical Research Communications. 229 (3): 922–9. doi:10.1006/bbrc.1996.1903. PMID 9005841.
• Thénot S, Henriquet C, Rochefort H, Cavaillès V (maj 1997). "Differential interaction of nuclear receptors with the putative human transcriptional coactivator hTIF1". The Journal of Biological Chemistry. 272 (18): 12062–8. doi:10.1074/jbc.272.18.12062. PMID 9115274.

Vanjski linkovi

Šablon:Modulatori retinoidnog receptora Ovaj članak uključuje tekst iz Nacionalne medicinske biblioteke Sjedinjenih Država, koji je u javnom vlasništvu.