DDX3Y

DDX3Y
Identifikatori
Aliasi	DDX3Y
Vanjski ID-jevi	OMIM: 400010 MGI: 1349406 HomoloGene: 55839 GeneCards: DDX3Y
Lokacija gena (čovjek)
Hrom.	Hromosom Y
Kraj	12,920,478 bp
Lokacija gena (miš)
Hrom.	Hromosom Y (miš)
Kraj	1,286,629 bp
Obrazac RNK ekspresije
	; ;
	Više referentnih podataka o ekspresiji
Ontologija gena
Molekularna funkcija	• vezivanje sa DNK; • nucleotide binding; • hydrolase activity; • ATP binding; • GO:0008026 helicase activity; • vezivanje sa RNK; • nucleic acid binding;
Ćelijska komponenta	• cytoplasmic ribonucleoprotein granule; • membrana; • jedro; • citoplazma; • citosol; • Jedarce;
Biološki proces	• translational initiation; • Regulacija ekspresije gena; • RNA secondary structure unwinding; • hromosomska segregacija;
	Izvori:Amigo / QuickGO
Ortolozi
	8653
	26900
	ENSG00000067048
	ENSMUSG00000069045
	O15523
	Q62095
	NM_001122665; NM_001302552; NM_004660; NM_001324195
	NM_012008
	NP_001116137; NP_001289481; NP_001311124; NP_004651
	NP_036138
	Wikipodaci
Pogledaj/uredi – čovjek	Pogledaj/uredi – miš

ATP-ovisna RNK-helikaza DDX3X je enzim koji je kod ljudi kodiran genom DDX3X.^[5]^[6]^[7]

Funkcija

Subćelijski promet

Proteini DEAD kutije, karakterizirani konzerviranim motivom Asp-Glu-Ala-Asp (DEAD), pretpostavljena su RNA helikaza. Uključeni su u brojne ćelijske procese koji uključuju izmjenu sekundarne strukture RNK, poput inicijacija translacije i preradu jedarne mitohondrijske RNK i sklapanje ribosoma i splajsosoma. Na osnovu njihovih obrazaca raspodjele, vjeruje se da su neki članovi ove porodice uključeni u embriogenezu, spermatogenezu i stanični rast i diobu. Ovaj gen kodira protein DEAD kutije, koji specifično komunicira s jezgrom proteina virusa hepatitisa C što rezultira promjenom unutarćelijske lokacije. Ovaj gen ima homolog smješten u nerekombinirajućem području Y hromozoma. Proteinska sekvenca je 91% identična između ovog gena i Y-povezanog homologa.^[7]

DDX3X obavlja svoje funkcije u ćelijskom jedru i citoplazmi, izlazeći iz jedra putem eksportin-1 / CRM1 jedarnog izvodnog puta. Prvobitno je objavljeno da je za ovu interakciju neophodan domen helikaze DDX3X, dok je za kanonske karakteristike puta prometa kod ljudi, nisu bili potrebni jedarni eksportni signal (NES) na DDX3X i Ran-GTP koji se vežu za exportin-1.^[8] Od tada je pokazano da DDX3X vezanje i promet eksportinom-1 ne zahtijeva DDX3X domen helikaze i da je eksplicitno NES- and Ran-GTP-ovisan.^[9]

Uloga u kanceru

DDX3X je uključen u mnogo različitih tipova karcinoma. Naprimjer, nenormalno se ispoljava u ćelijama raka epitela dojke, u kojima se njegova ekspresija aktivira pomoću HIF1A tokom hipoksija.^[10] Povećana ekspresija DDX3X pomoću HIF1A u hipoksiji pokreće se direktnim vezanjem HIF1A za HIF1A. Element odgovora, kako je verifikovano sa imunoprecipitacijom hromatina i testom reportera luciferaze. Budući da na ekspresiju DDX3X utiče aktivnost HIF1A, također je demonstrirana kolokalizacija ovih proteina u MDA-MB-231 ksenotransplantatnim uzorcima tumora. Saopćeno je da u HeLa ćelijama DDX3X kontrolira progresiju ćelijskog ciklusa, pomoću ciklina E1.^[11] Preciznije, pokazano je da se DDX3X direktno veže za 5´ UTR]] ciklina E1 i na taj način olakšava translaciju proteina. Pokazano je da pri povećanim nivoima proteina, ciklin E1 posreduje u tranziciji ulaska u S-fazu.

Aktivnost DDX3X utiče na preživljavanje, migraciju i proliferaciju melanoma.^[12] Ćelije melanoma s niskom ekspresijom DDX3X pokazuju visok migracijski kapacitet, nisku stopu proliferacije i smanjenu osjetljivost na vemurafenib. Iako su ćelije sa visokim ekspresijom DDX3X osjetljive na lijekove, proliferativnije su i manje migratorne. Ovi fenotipovi mogu se objasniti translacijskim efektima na faktor transkripcije melanoma MITF. 5 'UTR iRNK MITF-a sadrži složeni regulator RNK (IRES) koji je vezan i aktiviran putem DDX3X. Aktivacija IRES-a dovodi do translacije mITF MITF. Miševi kojima su ubrizgane ćelije melanoma sa deletiranim IRES, pokazuju agresivniju progresiju tumora, uključujući povećane plućne metastaze. Zanimljivo je da na DDX3X u melanomu vemurafenib utiče neotkrivenim mehanizmom. Nepoznato je kako prisustvo DDX3X regulira prisustvo vemurafeniba. Međutim, smanjeni nivoi DDX3X tokom uzimanja lijekova objašnjavaju razvoj ćelija otpornih na lijekove koji se često otkrivaju s niskom ekspresijom MITF.^[12]^[13]^[14]

Klinički značaj

Mutacije gena DDX3X povezane su sa meduloblastomom.^[15]^[16]^[17] U melanomu je niska ekspresija gena povezana sa lošim preživljavanjem bez udaljenih metastaza. Pored toga, nivo iRNK DDX3X-a je niži u odgovarajućem post-relapsu biopsije melanoma za pacijente koji primaju vemurafenib i kod tumora koji napreduju.

Također pogledajte

Reference

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000067048 - Ensembl, maj 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000069045 - Ensembl, maj 2017
^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ Lahn BT, Page DC (oktobar 1997). "Functional coherence of the human Y chromosome". Science. 278 (5338): 675–80. doi:10.1126/science.278.5338.675. PMID 9381176.
^ Park SH, Lee SG, Kim Y, Song K (Oct 1998). "Assignment of a human putative RNA helicase gene, DDX3, to human X chromosome bands p11.3→p11.23". Cytogenetics and Cell Genetics. 81 (3–4): 178–9. doi:10.1159/000015022. PMID 9730595.
^ ^a ^b "Entrez Gene: DDX3X DEAD (Asp-Glu-Ala-Asp) box polypeptide 3, X-linked".
^ Yedavalli VS, Neuveut C, Chi YH, Kleiman L, Jeang KT (oktobar 2004). "Requirement of DDX3 DEAD box RNA helicase for HIV-1 Rev-RRE export function". Cell (jezik: engleski). 119 (3): 381–92. doi:10.1016/j.cell.2004.09.029. PMID 15507209.
^ Heaton SM, Atkinson SC, Sweeney MN, Yang SN, Jans DA, Borg NA (septembar 2019). "Exportin-1-Dependent Nuclear Export of DEAD-box Helicase DDX3X is Central to its Role in Antiviral Immunity". Cells. 8 (10): 1181. doi:10.3390/cells8101181. PMID 31575075.
^ Botlagunta M, Krishnamachary B, Vesuna F, Winnard PT, Bol GM, Patel AH, Raman V (mart 2011). "Expression of DDX3 is directly modulated by hypoxia inducible factor-1 alpha in breast epithelial cells". PLOS ONE. 6 (3): e17563. doi:10.1371/journal.pone.0017563. PMC 3063174. PMID 21448281.
^ Lai MC, Chang WC, Shieh SY, Tarn WY (novembar 2010). "DDX3 regulates cell growth through translational control of cyclin E1". Molecular and Cellular Biology. 30 (22): 5444–53. doi:10.1128/MCB.00560-10. PMC 2976371. PMID 20837705.
^ ^a ^b Phung B, Cieśla M, Sanna A, Guzzi N, Beneventi G, Cao Thi Ngoc P, et al. (juni 2019). "The X-Linked DDX3X RNA Helicase Dictates Translation Reprogramming and Metastasis in Melanoma". Cell Reports. 27 (12): 3573–3586.e7. doi:10.1016/j.celrep.2019.05.069. PMID 31216476.
^ Müller J, Krijgsman O, Tsoi J, Robert L, Hugo W, Song C, et al. (decembar 2014). "Low MITF/AXL ratio predicts early resistance to multiple targeted drugs in melanoma". Nature Communications. 5 (1): 5712. doi:10.1038/ncomms6712. PMC 4428333. PMID 25502142.
^ Konieczkowski DJ, Johannessen CM, Abudayyeh O, Kim JW, Cooper ZA, Piris A, et al. (juli 2014). "A melanoma cell state distinction influences sensitivity to MAPK pathway inhibitors". Cancer Discovery. 4 (7): 816–27. doi:10.1158/2159-8290.CD-13-0424. PMC 4154497. PMID 24771846.
^ Robinson G, Parker M, Kranenburg TA, Lu C, Chen X, Ding L, et al. (august 2012). "Novel mutations target distinct subgroups of medulloblastoma". Nature. 488 (7409): 43–8. doi:10.1038/nature11213. PMC 3412905. PMID 22722829.
^ Jones DT, Jäger N, Kool M, Zichner T, Hutter B, Sultan M, et al. (august 2012). "Dissecting the genomic complexity underlying medulloblastoma". Nature. 488 (7409): 100–5. doi:10.1038/nature11284. PMC 3662966. PMID 22832583.
^ Pugh TJ, Weeraratne SD, Archer TC, Pomeranz Krummel DA, Auclair D, Bochicchio J, et al. (august 2012). "Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations". Nature. 488 (7409): 106–10. doi:10.1038/nature11329. PMC 3413789. PMID 22820256.

Dopunska literatura

Li L, Li HS, Pauza CD, Bukrinsky M, Zhao RY (2006). "Roles of HIV-1 auxiliary proteins in viral pathogenesis and host-pathogen interactions". Cell Research. 15 (11–12): 923–34. doi:10.1038/sj.cr.7290370. PMID 16354571.
Owsianka AM, Patel AH (maj 1999). "Hepatitis C virus core protein interacts with a human DEAD box protein DDX3". Virology. 257 (2): 330–40. doi:10.1006/viro.1999.9659. PMID 10329544.
Mamiya N, Worman HJ (maj 1999). "Hepatitis C virus core protein binds to a DEAD box RNA helicase". The Journal of Biological Chemistry. 274 (22): 15751–6. doi:10.1074/jbc.274.22.15751. PMID 10336476.
Yagüe J, Alvarez I, Rognan D, Ramos M, Vázquez J, de Castro JA (juni 2000). "An N-acetylated natural ligand of human histocompatibility leukocyte antigen (HLA)-B39. Classical major histocompatibility complex class I proteins bind peptides with a blocked NH(2) terminus in vivo". The Journal of Experimental Medicine. 191 (12): 2083–92. doi:10.1084/jem.191.12.2083. PMC 2193201. PMID 10859333.
Kim YS, Lee SG, Park SH, Song K (oktobar 2001). "Gene structure of the human DDX3 and chromosome mapping of its related sequences". Molecules and Cells. 12 (2): 209–14. PMID 11710523.
Li J, Hawkins IC, Harvey CD, Jennings JL, Link AJ, Patton JG (novembar 2003). "Regulation of alternative splicing by SRrp86 and its interacting proteins". Molecular and Cellular Biology. 23 (21): 7437–47. doi:10.1128/MCB.23.21.7437-7447.2003. PMC 207616. PMID 14559993.
Shu H, Chen S, Bi Q, Mumby M, Brekken DL (mart 2004). "Identification of phosphoproteins and their phosphorylation sites in the WEHI-231 B lymphoma cell line". Molecular & Cellular Proteomics. 3 (3): 279–86. doi:10.1074/mcp.D300003-MCP200. PMID 14729942.
Bouwmeester T, Bauch A, Ruffner H, Angrand PO, Bergamini G, Croughton K, Cruciat C, Eberhard D, Gagneur J, Ghidelli S, Hopf C, Huhse B, Mangano R, Michon AM, Schirle M, Schlegl J, Schwab M, Stein MA, Bauer A, Casari G, Drewes G, Gavin AC, Jackson DB, Joberty G, Neubauer G, Rick J, Kuster B, Superti-Furga G (februar 2004). "A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway". Nature Cell Biology. 6 (2): 97–105. doi:10.1038/ncb1086. PMID 14743216.
Yedavalli VS, Neuveut C, Chi YH, Kleiman L, Jeang KT (oktobar 2004). "Requirement of DDX3 DEAD box RNA helicase for HIV-1 Rev-RRE export function". Cell. 119 (3): 381–92. doi:10.1016/j.cell.2004.09.029. PMID 15507209.
Dayton AI (oktobar 2004). "Within you, without you: HIV-1 Rev and RNA export". Retrovirology. 1: 35. doi:10.1186/1742-4690-1-35. PMC 526764. PMID 15516266.
Krishnan V, Zeichner SL (decembar 2004). "Alterations in the expression of DEAD-box and other RNA binding proteins during HIV-1 replication". Retrovirology. 1: 42. doi:10.1186/1742-4690-1-42. PMC 543576. PMID 15588285.
Rush J, Moritz A, Lee KA, Guo A, Goss VL, Spek EJ, Zhang H, Zha XM, Polakiewicz RD, Comb MJ (januar 2005). "Immunoaffinity profiling of tyrosine phosphorylation in cancer cells". Nature Biotechnology. 23 (1): 94–101. doi:10.1038/nbt1046. PMID 15592455.
Tao WA, Wollscheid B, O'Brien R, Eng JK, Li XJ, Bodenmiller B, Watts JD, Hood L, Aebersold R (august 2005). "Quantitative phosphoproteome analysis using a dendrimer conjugation chemistry and tandem mass spectrometry". Nature Methods. 2 (8): 591–8. doi:10.1038/nmeth776. PMID 16094384.
Gevaert K, Staes A, Van Damme J, De Groot S, Hugelier K, Demol H, Martens L, Goethals M, Vandekerckhove J (septembar 2005). "Global phosphoproteome analysis on human HepG2 hepatocytes using reversed-phase diagonal LC". Proteomics. 5 (14): 3589–99. doi:10.1002/pmic.200401217. PMID 16097034.
Chang PC, Chi CW, Chau GY, Li FY, Tsai YH, Wu JC, Wu Lee YH (mart 2006). "DDX3, a DEAD box RNA helicase, is deregulated in hepatitis virus-associated hepatocellular carcinoma and is involved in cell growth control". Oncogene. 25 (14): 1991–2003. doi:10.1038/sj.onc.1209239. PMID 16301996.

PDB {{{1}}}

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000067048 - Ensembl, maj 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000069045 - 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.

[pmid9381176-5] Lahn BT, Page DC (oktobar 1997). "Functional coherence of the human Y chromosome". Science. 278 (5338): 675–80. doi:10.1126/science.278.5338.675. PMID 9381176.

[pmid9730595-6] Park SH, Lee SG, Kim Y, Song K (Oct 1998). "Assignment of a human putative RNA helicase gene, DDX3, to human X chromosome bands p11.3→p11.23". Cytogenetics and Cell Genetics. 81 (3–4): 178–9. doi:10.1159/000015022. PMID 9730595.

[entrez-7] "Entrez Gene: DDX3X DEAD (Asp-Glu-Ala-Asp) box polypeptide 3, X-linked".

[8] Yedavalli VS, Neuveut C, Chi YH, Kleiman L, Jeang KT (oktobar 2004). "Requirement of DDX3 DEAD box RNA helicase for HIV-1 Rev-RRE export function". Cell (jezik: engleski). 119 (3): 381–92. doi:10.1016/j.cell.2004.09.029. PMID 15507209.

[9] Heaton SM, Atkinson SC, Sweeney MN, Yang SN, Jans DA, Borg NA (septembar 2019). "Exportin-1-Dependent Nuclear Export of DEAD-box Helicase DDX3X is Central to its Role in Antiviral Immunity". Cells. 8 (10): 1181. doi:10.3390/cells8101181. PMID 31575075.

[:0-10] Botlagunta M, Krishnamachary B, Vesuna F, Winnard PT, Bol GM, Patel AH, Raman V (mart 2011). "Expression of DDX3 is directly modulated by hypoxia inducible factor-1 alpha in breast epithelial cells". PLOS ONE. 6 (3): e17563. doi:10.1371/journal.pone.0017563. PMC 3063174. PMID 21448281.

[:1-11] Lai MC, Chang WC, Shieh SY, Tarn WY (novembar 2010). "DDX3 regulates cell growth through translational control of cyclin E1". Molecular and Cellular Biology. 30 (22): 5444–53. doi:10.1128/MCB.00560-10. PMC 2976371. PMID 20837705.

[:2-12] Phung B, Cieśla M, Sanna A, Guzzi N, Beneventi G, Cao Thi Ngoc P, et al. (juni 2019). "The X-Linked DDX3X RNA Helicase Dictates Translation Reprogramming and Metastasis in Melanoma". Cell Reports. 27 (12): 3573–3586.e7. doi:10.1016/j.celrep.2019.05.069. PMID 31216476.

[13] Müller J, Krijgsman O, Tsoi J, Robert L, Hugo W, Song C, et al. (decembar 2014). "Low MITF/AXL ratio predicts early resistance to multiple targeted drugs in melanoma". Nature Communications. 5 (1): 5712. doi:10.1038/ncomms6712. PMC 4428333. PMID 25502142.

[14] Konieczkowski DJ, Johannessen CM, Abudayyeh O, Kim JW, Cooper ZA, Piris A, et al. (juli 2014). "A melanoma cell state distinction influences sensitivity to MAPK pathway inhibitors". Cancer Discovery. 4 (7): 816–27. doi:10.1158/2159-8290.CD-13-0424. PMC 4154497. PMID 24771846.

[15] Robinson G, Parker M, Kranenburg TA, Lu C, Chen X, Ding L, et al. (august 2012). "Novel mutations target distinct subgroups of medulloblastoma". Nature. 488 (7409): 43–8. doi:10.1038/nature11213. PMC 3412905. PMID 22722829.

[16] Jones DT, Jäger N, Kool M, Zichner T, Hutter B, Sultan M, et al. (august 2012). "Dissecting the genomic complexity underlying medulloblastoma". Nature. 488 (7409): 100–5. doi:10.1038/nature11284. PMC 3662966. PMID 22832583.

[17] Pugh TJ, Weeraratne SD, Archer TC, Pomeranz Krummel DA, Auclair D, Bochicchio J, et al. (august 2012). "Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations". Nature. 488 (7409): 106–10. doi:10.1038/nature11329. PMC 3413789. PMID 22820256.

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