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{{Short description|Protein-coding gene in humans}}
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{{Infobox_gene}}
{{Infobox_gene}}
'''ATP-dependent [[:en:Helicase#RNA helicases|RNA helicase]] DDX3X''' is an [[enzyme]] that in humans is encoded by the ''DDX3X'' [[gene]].<ref name="pmid9381176">{{cite journal |vauthors=Lahn BT, Page DC | title = Functional coherence of the human Y chromosome | journal = Science | volume = 278 | issue = 5338 | pages = 675–680 |date=Nov 1997 | pmid = 9381176 | pmc = | doi =10.1126/science.278.5338.675 }}</ref><ref name="pmid9730595">{{cite journal |vauthors=Park SH, Lee SG, Kim Y, Song K | title = Assignment of a human putative RNA helicase gene, DDX3, to human X chromosome bands p11.3→p11.23 | journal = Cytogenet Cell Genet | volume = 81 | issue = 3–4 | pages = 178–179 |date=Oct 1998 | pmid = 9730595 | pmc = | doi =10.1159/000015022 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: DDX3X DEAD (Asp-Glu-Ala-Asp) box polypeptide 3, X-linked| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1654| accessdate = }}</ref>
'''ATP-dependent [[:en:Helicase#RNA helicases|RNA helicase]] DDX3X''' is an [[enzyme]] that in humans is encoded by the ''DDX3X'' [[gene]].<ref name="pmid9381176">{{cite journal | vauthors = Lahn BT, Page DC | title = Functional coherence of the human Y chromosome | journal = Science | volume = 278 | issue = 5338 | pages = 675–80 | date = October 1997 | pmid = 9381176 | doi = 10.1126/science.278.5338.675 | bibcode = 1997Sci...278..675L }}</ref><ref name="pmid9730595">{{cite journal | vauthors = Park SH, Lee SG, Kim Y, Song K | title = Assignment of a human putative RNA helicase gene, DDX3, to human X chromosome bands p11.3→p11.23 | journal = Cytogenetics and Cell Genetics | volume = 81 | issue = 3–4 | pages = 178–9 | date = Oct 1998 | pmid = 9730595 | doi = 10.1159/000015022 | s2cid = 46774908 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: DDX3X DEAD (Asp-Glu-Ala-Asp) box polypeptide 3, X-linked| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1654 }}</ref>


== Function ==
== Function ==


DEAD box proteins, characterized by the conserved motif Asp-Glu-Ala-Asp (DEAD), are putative RNA helicases. They are implicated in a number of cellular processes involving alteration of RNA secondary structure such as translation initiation, nuclear and mitochondrial splicing, and ribosome and spliceosome assembly. Based on their distribution patterns, some members of this family are believed to be involved in embryogenesis, spermatogenesis, and cellular growth and division. This gene encodes a DEAD box protein, which interacts specifically with hepatitis C virus core protein resulting a change in intracellular location. This gene has a homolog located in the nonrecombining region of the Y chromosome. The protein sequence is 91% identical between this gene and the Y-linked homolog.<ref name="entrez"/>
[[DExD/H box proteins|DEAD box proteins]], characterized by the conserved motif Asp-Glu-Ala-Asp (DEAD), are putative RNA [[helicase]]s. They are implicated in a number of cellular processes involving alteration of RNA secondary structure such as [[Eukaryotic translation#Initiation|translation initiation]], nuclear and mitochondrial [[RNA splicing|splicing]], and [[ribosome]] and [[spliceosome]] assembly. Based on their distribution patterns, some members of this family are believed to be involved in embryogenesis, spermatogenesis, and cellular growth and division. This gene encodes a DEAD box protein, which interacts specifically with hepatitis C virus core protein resulting a change in intracellular location. This gene has a homolog located in the nonrecombining region of the Y chromosome. The protein sequence is 91% identical between this gene and the Y-linked homolog.<ref name="entrez"/>

== Sub-cellular trafficking ==
DDX3X performs its functions in the cell [[Cell nucleus|nucleus]] and [[cytoplasm]], exiting the nucleus via the [[XPO1|exportin-1/CRM1 nuclear export pathway]]. It was initially reported that the DDX3X helicase domain was necessary for this interaction, while the canonical features of the trafficking pathway, namely the presence of a [[Nuclear export signal|nuclear export signal (NES)]] on DDX3X and [[Ran (protein)|Ran-GTP]] binding to exportin-1, were dispensable.<ref>{{cite journal | vauthors = Yedavalli VS, Neuveut C, Chi YH, Kleiman L, Jeang KT | title = Requirement of DDX3 DEAD box RNA helicase for HIV-1 Rev-RRE export function | language = en | journal = Cell | volume = 119 | issue = 3 | pages = 381–92 | date = October 2004 | pmid = 15507209 | doi = 10.1016/j.cell.2004.09.029 | doi-access = free }}</ref> DDX3X binding to, and trafficking by, exportin-1 has since been shown not to require the DDX3X helicase domain and be explicitly NES- and Ran-GTP-dependent.<ref>{{cite journal | vauthors = Heaton SM, Atkinson SC, Sweeney MN, Yang SN, Jans DA, Borg NA | title = Exportin-1-Dependent Nuclear Export of DEAD-box Helicase DDX3X is Central to its Role in Antiviral Immunity | journal = Cells | volume = 8 | issue = 10 | pages = 1181 | date = September 2019 | pmid = 31575075 | doi = 10.3390/cells8101181 | pmc = 6848931 | doi-access = free }}</ref>


== Role in cancer ==
== Role in cancer ==
⚫
DDX3X is involved in many different types of cancer. For example, it is abnormally expressed in breast epithelial cancer cells in which its expression is activated by [[:en:HIF1A|HIF1A]] during [[:en:Tumor hypoxia|hypoxia]].<ref name=":0">{{Cite web|url = http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0017563|title = Expression of DDX3 is directly modulated by hypoxia inducible factor-1 alpha in breast epithelial cells|date = 2011-03-23|accessdate = |website = |publisher = PLoS ONE|doi = 10.1371/journal.pone.0017563}}</ref> Increased expression of DDX3X by HIF1A in hypoxia is initiated by the direct binding of HIF1A to the HIF1A [[:en:Transcription factor#Response elements|response element]],<ref name=":0" /> as verified with [[:en:Chromatin immunoprecipitation|chromatin immunoprecipitation]] and [[:en:Luciferase|luciferase reporter assay]]. Since the expression of DDX3X is affected by the activity of HIF1A, the co-localization of these proteins has also been demonstrated in MDA-MB-231 [[:en:Xenograft|xenograft]] tumor samples.<ref name=":0" />


⚫
DDX3X is involved in many different types of cancer. For example, it is abnormally expressed in breast epithelial cancer cells in which its expression is activated by [[:en:HIF1A|HIF1A]] during [[:en:Tumor hypoxia|hypoxia]].<ref name=":0">{{cite journal | vauthors = Botlagunta M, Krishnamachary B, Vesuna F, Winnard PT, Bol GM, Patel AH, Raman V | title = Expression of DDX3 is directly modulated by hypoxia inducible factor-1 alpha in breast epithelial cells | journal = PLOS ONE | volume = 6 | issue = 3 | pages = e17563 | date = March 2011 | pmid = 21448281 | doi = 10.1371/journal.pone.0017563 | pmc=3063174| bibcode = 2011PLoSO...617563B | doi-access = free }}</ref> Increased expression of DDX3X by HIF1A in hypoxia is initiated by the direct binding of HIF1A to the HIF1A [[:en:Transcription factor#Response elements|response element]],<ref name=":0" /> as verified with [[:en:Chromatin immunoprecipitation|chromatin immunoprecipitation]] and [[:en:Luciferase|luciferase reporter assay]]. Since the expression of DDX3X is affected by the activity of HIF1A, the co-localization of these proteins has also been demonstrated in [[MDA-MB-231]] [[:en:Xenograft|xenograft]] tumor samples.<ref name=":0" />
⚫
In [[:en:HeLa|HeLa cells]] DDX3X is reported to control cell cycle progression through [[:en:Cyclin E1|Cyclin E1]].<ref name=":1">{{Cite web|url = http://mcb.asm.org/content/30/22/5444.long|title = DDX3 Regulates Cell Growth through Translational Control of Cyclin E1|date = November 2010|accessdate = |website = |publisher = Molecular and Cellular Biology|doi = 10.1128/MCB.00560-10}}</ref> More specifically, DDX3X was shown to directly bind to the [[:en:Five prime untranslated region|5´ UTR]] of Cyclin E1 and thereby facilitating the translation of the protein. Increased protein levels of Cyclin E1 was demonstrated to mediate the transition of [[:en:S phase|S phase]] entry.<ref name=":1" />

⚫
In [[:en:HeLa|HeLa cells]] DDX3X is reported to control cell cycle progression through [[:en:Cyclin E1|Cyclin E1]].<ref name=":1">{{cite journal | vauthors = Lai MC, Chang WC, Shieh SY, Tarn WY | title = DDX3 regulates cell growth through translational control of cyclin E1 | journal = Molecular and Cellular Biology | volume = 30 | issue = 22 | pages = 5444–53 | date = November 2010 | pmid = 20837705 | doi = 10.1128/MCB.00560-10 | pmc=2976371}}</ref> More specifically, DDX3X was shown to directly bind to the [[:en:Five prime untranslated region|5´ UTR]] of Cyclin E1 and thereby facilitating the translation of the protein. Increased protein levels of Cyclin E1 was demonstrated to mediate the transition of [[:en:S phase|S phase]] entry.<ref name=":1" />

Melanoma survival, migration and proliferation is affected by DDX3X activity.<ref name=":2">{{cite journal | vauthors = Phung B, Cieśla M, Sanna A, Guzzi N, Beneventi G, Cao Thi Ngoc P, Lauss M, Cabrita R, Cordero E, Bosch A, Rosengren F, Häkkinen J, Griewank K, Paschen A, Harbst K, Olsson H, Ingvar C, Carneiro A, Tsao H, Schadendorf D, Pietras K, Bellodi C, Jönsson G | title = The X-Linked DDX3X RNA Helicase Dictates Translation Reprogramming and Metastasis in Melanoma | journal = Cell Reports | volume = 27 | issue = 12 | pages = 3573–3586.e7 | date = June 2019 | pmid = 31216476 | doi = 10.1016/j.celrep.2019.05.069 | doi-access = free }}</ref> Melanoma cells with low DDX3X expression exhibit a high migratory capacity, low proliferation rate and reduced [[vemurafenib]] sensitivity. While high DDX3X expressing cells are drug sensitive, more proliferative and less migratory. These phenotypes can be explained by the translational effects on the melanoma transcription factor [[Microphthalmia-associated transcription factor|''MITF'']].<ref name=":2" /> The 5' UTR of the [[Microphthalmia-associated transcription factor|MITF]] mRNA contains a complex RNA regulon ([[Internal ribosome entry site|IRES]]) that is bound and activated by DDX3X. Activation of the IRES leads to translation of the MITF mRNA. Mice injected with melanoma cells with a deleted IRES display more aggressive tumor progression including increased lung [[metastasis]].<ref name=":2" /> Interestingly, the DDX3X in melanoma is affected by vemurafenib via an undiscovered [[Signal transduction|mechanism]]. It is unknown how ''DDX3X'' is downregulated by the presence of vemurafenib. However, reduced levels of ''DDX3X'' during drug treatment explains the development of drug resistant cells frequently detected with low ''MITF'' expression.<ref name=":2" /><ref>{{cite journal | vauthors = Müller J, Krijgsman O, Tsoi J, Robert L, Hugo W, Song C, Kong X, Possik PA, Cornelissen-Steijger PD, Geukes Foppen MH, Kemper K, Goding CR, McDermott U, Blank C, Haanen J, Graeber TG, Ribas A, Lo RS, Peeper DS | title = Low MITF/AXL ratio predicts early resistance to multiple targeted drugs in melanoma | journal = Nature Communications | volume = 5 | issue = 1 | pages = 5712 | date = December 2014 | pmid = 25502142 | pmc = 4428333 | doi = 10.1038/ncomms6712 | bibcode = 2014NatCo...5.5712M }}</ref><ref>{{cite journal | vauthors = Konieczkowski DJ, Johannessen CM, Abudayyeh O, Kim JW, Cooper ZA, Piris A, Frederick DT, Barzily-Rokni M, Straussman R, Haq R, Fisher DE, Mesirov JP, Hahn WC, Flaherty KT, Wargo JA, Tamayo P, Garraway LA | title = A melanoma cell state distinction influences sensitivity to MAPK pathway inhibitors | journal = Cancer Discovery | volume = 4 | issue = 7 | pages = 816–27 | date = July 2014 | pmid = 24771846 | pmc = 4154497 | doi = 10.1158/2159-8290.CD-13-0424 }}</ref>


== Clinical significance ==
== Clinical significance ==


Mutations of the ''DDX3X'' gene are also associated with [[medulloblastoma]].<ref>{{cite journal |vauthors=Robinson G, Parker M, Kranenburg TA | title = Novel mutations target distinct subgroups of medulloblastoma | journal = Nature |date=June 2012 | doi = 10.1038/nature11213 | volume=488 | issue=7409|display-authors=etal | pages=43–48}}</ref><ref>{{cite journal |vauthors=Jones TW, Jäger N, Kool M | title = Dissecting the genomic complexity underlying medulloblastoma | journal = Nature |date=July 2012 | doi = 10.1038/nature11284 | pmid=22832583 | volume=488 | issue=7409 | pages=100–5 | pmc=3662966|display-authors=etal}}</ref><ref>{{cite journal |vauthors=Pugh TJ, Weeraratne SD, Archer TC | title = Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations | journal = Nature |date=July 2012 | doi = 10.1038/nature11329 |display-authors=etal | volume=488 | pages=106–110}}</ref>
Mutations of the ''DDX3X'' gene are associated with [[medulloblastoma]].<ref>{{cite journal | vauthors = Robinson G, Parker M, Kranenburg TA, Lu C, Chen X, Ding L, Phoenix TN, Hedlund E, Wei L, Zhu X, Chalhoub N, Baker SJ, Huether R, Kriwacki R, Curley N, Thiruvenkatam R, Wang J, Wu G, Rusch M, Hong X, Becksfort J, Gupta P, Ma J, Easton J, Vadodaria B, Onar-Thomas A, Lin T, Li S, Pounds S, Paugh S, Zhao D, Kawauchi D, Roussel MF, Finkelstein D, Ellison DW, Lau CC, Bouffet E, Hassall T, Gururangan S, Cohn R, Fulton RS, Fulton LL, Dooling DJ, Ochoa K, Gajjar A, Mardis ER, Wilson RK, Downing JR, Zhang J, Gilbertson RJ | title = Novel mutations target distinct subgroups of medulloblastoma | journal = Nature | volume = 488 | issue = 7409 | pages = 43–8 | date = August 2012 | pmid = 22722829 | doi = 10.1038/nature11213 | pmc=3412905| bibcode = 2012Natur.488...43R }}</ref><ref>{{cite journal | vauthors = Jones DT, Jäger N, Kool M, Zichner T, Hutter B, Sultan M, Cho YJ, Pugh TJ, Hovestadt V, Stütz AM, Rausch T, Warnatz HJ, Ryzhova M, Bender S, Sturm D, Pleier S, Cin H, Pfaff E, Sieber L, Wittmann A, Remke M, Witt H, Hutter S, Tzaridis T, Weischenfeldt J, Raeder B, Avci M, Amstislavskiy V, Zapatka M, Weber UD, Wang Q, Lasitschka B, Bartholomae CC, Schmidt M, von Kalle C, Ast V, Lawerenz C, Eils J, Kabbe R, Benes V, van Sluis P, Koster J, Volckmann R, Shih D, Betts MJ, Russell RB, Coco S, Tonini GP, Schüller U, Hans V, Graf N, Kim YJ, Monoranu C, Roggendorf W, Unterberg A, Herold-Mende C, Milde T, Kulozik AE, von Deimling A, Witt O, Maass E, Rössler J, Ebinger M, Schuhmann MU, Frühwald MC, Hasselblatt M, Jabado N, Rutkowski S, von Bueren AO, Williamson D, Clifford SC, McCabe MG, Collins VP, Wolf S, Wiemann S, Lehrach H, Brors B, Scheurlen W, Felsberg J, Reifenberger G, Northcott PA, Taylor MD, Meyerson M, Pomeroy SL, Yaspo ML, Korbel JO, Korshunov A, Eils R, Pfister SM, Lichter P | title = Dissecting the genomic complexity underlying medulloblastoma | journal = Nature | volume = 488 | issue = 7409 | pages = 100–5 | date = August 2012 | pmid = 22832583 | pmc = 3662966 | doi = 10.1038/nature11284 | bibcode = 2012Natur.488..100J }}</ref><ref>{{cite journal | vauthors = Pugh TJ, Weeraratne SD, Archer TC, Pomeranz Krummel DA, Auclair D, Bochicchio J, Carneiro MO, Carter SL, Cibulskis K, Erlich RL, Greulich H, Lawrence MS, Lennon NJ, McKenna A, Meldrim J, Ramos AH, Ross MG, Russ C, Shefler E, Sivachenko A, Sogoloff B, Stojanov P, Tamayo P, Mesirov JP, Amani V, Teider N, Sengupta S, Francois JP, Northcott PA, Taylor MD, Yu F, Crabtree GR, Kautzman AG, Gabriel SB, Getz G, Jäger N, Jones DT, Lichter P, Pfister SM, Roberts TM, Meyerson M, Pomeroy SL, Cho YJ | title = Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations | journal = Nature | volume = 488 | issue = 7409 | pages = 106–10 | date = August 2012 | pmid = 22820256 | pmc = 3413789 | doi = 10.1038/nature11329 | bibcode = 2012Natur.488..106P }}</ref> In melanoma the low expression of the gene is linked to a poor [[Disease-free survival|distant metastasis free survival]].<ref name=":2" /> In addition, the mRNA level of DDX3X is lower in matched post-relapse melanoma biopsies for patients receiving [[vemurafenib]] and in progressing tumors.

Mutations of the DDX3X gene also cause [[DDX3X syndrome]], which affects predominantly females and presents with [[Developmental disability|developmental delay]] or disability, [[autism]], [[Attention deficit hyperactivity disorder|ADHD]], and [[Hypotonia|low muscle tone]].

== See also ==

*[[Eukaryotic translation]]
*[[DExD/H box proteins]]
*[[DHX29]]


==References==
== References ==
{{reflist}}
{{reflist}}


==Further reading==
== Further reading ==
{{refbegin | 2}}
{{refbegin | 2}}
*{{cite journal | author=Li L |title=Roles of HIV-1 auxiliary proteins in viral pathogenesis and host-pathogen interactions |journal=Cell Res. |volume=15 |issue= 11–12 |pages= 923–934 |year= 2006 |pmid= 16354571 |doi= 10.1038/sj.cr.7290370 |name-list-format=vanc| author2=Li HS | author3=Pauza CD | display-authors=3 | last4=Bukrinsky | first4=Michael | last5=Zhao | first5=Richard Y }}
* {{cite journal | vauthors = Li L, Li HS, Pauza CD, Bukrinsky M, Zhao RY | title = Roles of HIV-1 auxiliary proteins in viral pathogenesis and host-pathogen interactions | journal = Cell Research | volume = 15 | issue = 11–12 | pages = 923–34 | year = 2006 | pmid = 16354571 | doi = 10.1038/sj.cr.7290370 | doi-access = free }}
*{{cite journal |vauthors=Owsianka AM, Patel AH |title=Hepatitis C virus core protein interacts with a human DEAD box protein DDX3 |journal=Virology |volume=257 |issue= 2 |pages= 330–340 |year= 1999 |pmid= 10329544 |doi= 10.1006/viro.1999.9659 }}
* {{cite journal | vauthors = Owsianka AM, Patel AH | title = Hepatitis C virus core protein interacts with a human DEAD box protein DDX3 | journal = Virology | volume = 257 | issue = 2 | pages = 330–40 | date = May 1999 | pmid = 10329544 | doi = 10.1006/viro.1999.9659 | doi-access = free }}
*{{cite journal |vauthors=Mamiya N, Worman HJ |title=Hepatitis C virus core protein binds to a DEAD box RNA helicase |journal=J. Biol. Chem. |volume=274 |issue= 22 |pages= 15751–15756 |year= 1999 |pmid= 10336476 |doi=10.1074/jbc.274.22.15751 }}
* {{cite journal | vauthors = Mamiya N, Worman HJ | title = Hepatitis C virus core protein binds to a DEAD box RNA helicase | journal = The Journal of Biological Chemistry | volume = 274 | issue = 22 | pages = 15751–6 | date = May 1999 | pmid = 10336476 | doi = 10.1074/jbc.274.22.15751 | doi-access = free }}
*{{cite journal | author=Yagüe J |title=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 |journal=J. Exp. Med. |volume=191 |issue= 12 |pages= 2083–2092 |year= 2000 |pmid= 10859333 |doi=10.1084/jem.191.12.2083 | pmc=2193201 |name-list-format=vanc| author2=Alvarez I | author3=Rognan D | display-authors=3 | last4=Ramos | first4=M | last5=Vázquez | first5=J | last6=De Castro | first6=JA }}
* {{cite journal | vauthors = Yagüe J, Alvarez I, Rognan D, Ramos M, Vázquez J, de Castro JA | title = 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 | journal = The Journal of Experimental Medicine | volume = 191 | issue = 12 | pages = 2083–92 | date = June 2000 | pmid = 10859333 | pmc = 2193201 | doi = 10.1084/jem.191.12.2083 }}
*{{cite journal |vauthors=Kim YS, Lee SG, Park SH, Song K |title=Gene structure of the human DDX3 and chromosome mapping of its related sequences |journal=Mol. Cells |volume=12 |issue= 2 |pages= 209–14 |year= 2002 |pmid= 11710523 |doi= }}
* {{cite journal | vauthors = Kim YS, Lee SG, Park SH, Song K | title = Gene structure of the human DDX3 and chromosome mapping of its related sequences | journal = Molecules and Cells | volume = 12 | issue = 2 | pages = 209–14 | date = October 2001 | doi = 10.1016/S1016-8478(23)17085-3 | pmid = 11710523 | doi-access = free }}
* {{cite journal | vauthors = Li J, Hawkins IC, Harvey CD, Jennings JL, Link AJ, Patton JG | title = Regulation of alternative splicing by SRrp86 and its interacting proteins | journal = Molecular and Cellular Biology | volume = 23 | issue = 21 | pages = 7437–47 | date = November 2003 | pmid = 14559993 | pmc = 207616 | doi = 10.1128/MCB.23.21.7437-7447.2003 }}
*{{cite journal | author=Strausberg RL |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899–16903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899 | pmc=139241 |name-list-format=vanc| author2=Feingold EA | author3=Grouse LH | display-authors=3 | last4=Derge | first4=JG | last5=Klausner | first5=RD | last6=Collins | first6=FS | last7=Wagner | first7=L | last8=Shenmen | first8=CM | last9=Schuler | first9=GD }}
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* {{cite journal | vauthors = Shu H, Chen S, Bi Q, Mumby M, Brekken DL | title = Identification of phosphoproteins and their phosphorylation sites in the WEHI-231 B lymphoma cell line | journal = Molecular & Cellular Proteomics | volume = 3 | issue = 3 | pages = 279–86 | date = March 2004 | pmid = 14729942 | doi = 10.1074/mcp.D300003-MCP200 | doi-access = free }}
*{{cite journal | author=Li J |title=Regulation of alternative splicing by SRrp86 and its interacting proteins |journal=Mol. Cell. Biol. |volume=23 |issue= 21 |pages= 7437–7447 |year= 2003 |pmid= 14559993 |doi=10.1128/MCB.23.21.7437-7447.2003 | pmc=207616 |name-list-format=vanc| author2=Hawkins IC | author3=Harvey CD | display-authors=3 | last4=Jennings | first4=J. L. | last5=Link | first5=A. J. | last6=Patton | first6=J. G. }}
* {{cite journal | vauthors = 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 | title = A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway | journal = Nature Cell Biology | volume = 6 | issue = 2 | pages = 97–105 | date = February 2004 | pmid = 14743216 | doi = 10.1038/ncb1086 | s2cid = 11683986 }}
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*{{cite journal | author=Shu H |title=Identification of phosphoproteins and their phosphorylation sites in the WEHI-231 B lymphoma cell line |journal=Mol. Cell Proteomics |volume=3 |issue= 3 |pages= 279–286 |year= 2004 |pmid= 14729942 |doi= 10.1074/mcp.D300003-MCP200 |name-list-format=vanc| author2=Chen S | author3=Bi Q | display-authors=3 | last4=Mumby | first4=M | last5=Brekken | first5=DL }}
* {{cite journal | vauthors = Yedavalli VS, Neuveut C, Chi YH, Kleiman L, Jeang KT | title = Requirement of DDX3 DEAD box RNA helicase for HIV-1 Rev-RRE export function | journal = Cell | volume = 119 | issue = 3 | pages = 381–92 | date = October 2004 | pmid = 15507209 | doi = 10.1016/j.cell.2004.09.029 | doi-access = free }}
*{{cite journal | author=Bouwmeester T |title=A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway |journal=Nat. Cell Biol. |volume=6 |issue= 2 |pages= 97–105 |year= 2004 |pmid= 14743216 |doi= 10.1038/ncb1086 |name-list-format=vanc| author2=Bauch A | author3=Ruffner H | display-authors=3 | last4=Angrand | first4=Pierre-Olivier | last5=Bergamini | first5=Giovanna | last6=Croughton | first6=Karen | last7=Cruciat | first7=Cristina | last8=Eberhard | first8=Dirk | last9=Gagneur | first9=Julien }}
* {{cite journal | vauthors = Dayton AI | title = Within you, without you: HIV-1 Rev and RNA export | journal = Retrovirology | volume = 1 | pages = 35 | date = October 2004 | pmid = 15516266 | pmc = 526764 | doi = 10.1186/1742-4690-1-35 | doi-access = free }}
*{{cite journal | author=Gerhard DS |title=The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC) |journal=Genome Res. |volume=14 |issue= 10B |pages= 2121–2127 |year= 2004 |pmid= 15489334 |doi= 10.1101/gr.2596504 | pmc=528928 |name-list-format=vanc| author2=Wagner L | author3=Feingold EA | display-authors=3 | last4=Shenmen | first4=CM | last5=Grouse | first5=LH | last6=Schuler | first6=G | last7=Klein | first7=SL | last8=Old | first8=S | last9=Rasooly | first9=R }}
*{{cite journal | author=Yedavalli VS |title=Requirement of DDX3 DEAD box RNA helicase for HIV-1 Rev-RRE export function |journal=Cell |volume=119 |issue= 3 |pages= 381–392 |year= 2004 |pmid= 15507209 |doi= 10.1016/j.cell.2004.09.029 |name-list-format=vanc| author2=Neuveut C | author3=Chi YH | display-authors=3 | last4=Kleiman | first4=Lawrence | last5=Jeang | first5=Kuan-Teh }}
* {{cite journal | vauthors = Krishnan V, Zeichner SL | title = Alterations in the expression of DEAD-box and other RNA binding proteins during HIV-1 replication | journal = Retrovirology | volume = 1 | pages = 42 | date = December 2004 | pmid = 15588285 | pmc = 543576 | doi = 10.1186/1742-4690-1-42 | doi-access = free }}
*{{cite journal | author=Dayton AI |title=Within you, without you: HIV-1 Rev and RNA export |journal=Retrovirology |volume=1 |issue= |pages= 35 |year= 2006 |pmid= 15516266 |doi= 10.1186/1742-4690-1-35 | pmc=526764 }}
* {{cite journal | vauthors = Rush J, Moritz A, Lee KA, Guo A, Goss VL, Spek EJ, Zhang H, Zha XM, Polakiewicz RD, Comb MJ | title = Immunoaffinity profiling of tyrosine phosphorylation in cancer cells | journal = Nature Biotechnology | volume = 23 | issue = 1 | pages = 94–101 | date = January 2005 | pmid = 15592455 | doi = 10.1038/nbt1046 | s2cid = 7200157 }}
*{{cite journal |vauthors=Krishnan V, Zeichner SL |title=Alterations in the expression of DEAD-box and other RNA binding proteins during HIV-1 replication |journal=Retrovirology |volume=1 |issue= |pages= 42 |year= 2006 |pmid= 15588285 |doi= 10.1186/1742-4690-1-42 | pmc=543576 }}
* {{cite journal | vauthors = Tao WA, Wollscheid B, O'Brien R, Eng JK, Li XJ, Bodenmiller B, Watts JD, Hood L, Aebersold R | title = Quantitative phosphoproteome analysis using a dendrimer conjugation chemistry and tandem mass spectrometry | journal = Nature Methods | volume = 2 | issue = 8 | pages = 591–8 | date = August 2005 | pmid = 16094384 | doi = 10.1038/nmeth776 | s2cid = 20475874 }}
* {{cite journal | vauthors = Gevaert K, Staes A, Van Damme J, De Groot S, Hugelier K, Demol H, Martens L, Goethals M, Vandekerckhove J | title = Global phosphoproteome analysis on human HepG2 hepatocytes using reversed-phase diagonal LC | journal = Proteomics | volume = 5 | issue = 14 | pages = 3589–99 | date = September 2005 | pmid = 16097034 | doi = 10.1002/pmic.200401217 | s2cid = 895879 | url = https://biblio.ugent.be/publication/339260/file/2059709 }}
*{{cite journal | author=Rush J |title=Immunoaffinity profiling of tyrosine phosphorylation in cancer cells |journal=Nat. Biotechnol. |volume=23 |issue= 1 |pages= 94–101 |year= 2005 |pmid= 15592455 |doi= 10.1038/nbt1046 |name-list-format=vanc| author2=Moritz A | author3=Lee KA | display-authors=3 | last4=Guo | first4=Ailan | last5=Goss | first5=Valerie L | last6=Spek | first6=Erik J | last7=Zhang | first7=Hui | last8=Zha | first8=Xiang-Ming | last9=Polakiewicz | first9=Roberto D }}
⚫
* {{cite journal | vauthors = Chang PC, Chi CW, Chau GY, Li FY, Tsai YH, Wu JC, Wu Lee YH | title = DDX3, a DEAD box RNA helicase, is deregulated in hepatitis virus-associated hepatocellular carcinoma and is involved in cell growth control | journal = Oncogene | volume = 25 | issue = 14 | pages = 1991–2003 | date = March 2006 | pmid = 16301996 | doi = 10.1038/sj.onc.1209239 | doi-access = free }}
*{{cite journal | author=Tao WA |title=Quantitative phosphoproteome analysis using a dendrimer conjugation chemistry and tandem mass spectrometry |journal=Nat. Methods |volume=2 |issue= 8 |pages= 591–598 |year= 2005 |pmid= 16094384 |doi= 10.1038/nmeth776 |name-list-format=vanc| author2=Wollscheid B | author3=O'Brien R | display-authors=3 | last4=Eng | first4=Jimmy K | last5=Li | first5=Xiao-jun | last6=Bodenmiller | first6=Bernd | last7=Watts | first7=Julian D | last8=Hood | first8=Leroy | last9=Aebersold | first9=Ruedi }}
*{{cite journal | author=Gevaert K |title=Global phosphoproteome analysis on human HepG2 hepatocytes using reversed-phase diagonal LC |journal=Proteomics |volume=5 |issue= 14 |pages= 3589–3599 |year= 2006 |pmid= 16097034 |doi= 10.1002/pmic.200401217 |name-list-format=vanc| author2=Staes A | author3=Van Damme J | display-authors=3 | last4=De Groot | first4=Sara | last5=Hugelier | first5=Koen | last6=Demol | first6=Hans | last7=Martens | first7=Lennart | last8=Goethals | first8=Marc | last9=Vandekerckhove | first9=Joël }}
*{{cite journal | author=Rual JF |title=Towards a proteome-scale map of the human protein-protein interaction network |journal=Nature |volume=437 |issue= 7062 |pages= 1173–1178 |year= 2005 |pmid= 16189514 |doi= 10.1038/nature04209 |name-list-format=vanc| author2=Venkatesan K | author3=Hao T | display-authors=3 | last4=Hirozane-Kishikawa | first4=Tomoko | last5=Dricot | first5=Amélie | last6=Li | first6=Ning | last7=Berriz | first7=Gabriel F. | last8=Gibbons | first8=Francis D. | last9=Dreze | first9=Matija }}
⚫
*{{cite journal | author=Chang PC |title=DDX3, a DEAD box RNA helicase, is deregulated in hepatitis virus-associated hepatocellular carcinoma and is involved in cell growth control |journal=Oncogene |volume=25 |issue= 14 |pages= 1991–2003 |year= 2006 |pmid= 16301996 |doi= 10.1038/sj.onc.1209239 |name-list-format=vanc| author2=Chi CW | author3=Chau GY | display-authors=3 | last4=Li | first4=F-Y | last5=Tsai | first5=Y-H | last6=Wu | first6=J-C | last7=Wu Lee | first7=Y-H }}
{{refend}}
{{refend}}


Latest revision as of 06:55, 15 April 2024

DDX3X
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesDDX3X, DBX, DDX14, DDX3, HLP2, CAP-Rf, MRX102, DEAD-box helicase 3, X-linked, DEAD-box helicase 3 X-linked, MRXSSB
External IDsOMIM: 300160; MGI: 103064; HomoloGene: 3425; GeneCards: DDX3X; OMA:DDX3X - orthologs
Orthologs
SpeciesHumanMouse
Entrez

1654

13205

Ensembl

ENSG00000215301

ENSMUSG00000000787

UniProt

O00571

Q62167

RefSeq (mRNA)

NM_001193416
NM_001193417
NM_001356
NM_024005
NM_001363819

NM_010028
NM_008015

RefSeq (protein)

NP_001180345
NP_001180346
NP_001347
NP_001350748

NP_034158

Location (UCSC)Chr X: 41.33 – 41.36 MbChr X: 13.15 – 13.16 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

ATP-dependent RNA helicase DDX3X is an enzyme that in humans is encoded by the DDX3X gene.[5][6][7]

Function

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DEAD box proteins, characterized by the conserved motif Asp-Glu-Ala-Asp (DEAD), are putative RNA helicases. They are implicated in a number of cellular processes involving alteration of RNA secondary structure such as translation initiation, nuclear and mitochondrial splicing, and ribosome and spliceosome assembly. Based on their distribution patterns, some members of this family are believed to be involved in embryogenesis, spermatogenesis, and cellular growth and division. This gene encodes a DEAD box protein, which interacts specifically with hepatitis C virus core protein resulting a change in intracellular location. This gene has a homolog located in the nonrecombining region of the Y chromosome. The protein sequence is 91% identical between this gene and the Y-linked homolog.[7]

Sub-cellular trafficking

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DDX3X performs its functions in the cell nucleus and cytoplasm, exiting the nucleus via the exportin-1/CRM1 nuclear export pathway. It was initially reported that the DDX3X helicase domain was necessary for this interaction, while the canonical features of the trafficking pathway, namely the presence of a nuclear export signal (NES) on DDX3X and Ran-GTP binding to exportin-1, were dispensable.[8] DDX3X binding to, and trafficking by, exportin-1 has since been shown not to require the DDX3X helicase domain and be explicitly NES- and Ran-GTP-dependent.[9]

Role in cancer

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DDX3X is involved in many different types of cancer. For example, it is abnormally expressed in breast epithelial cancer cells in which its expression is activated by HIF1A during hypoxia.[10] Increased expression of DDX3X by HIF1A in hypoxia is initiated by the direct binding of HIF1A to the HIF1A response element,[10] as verified with chromatin immunoprecipitation and luciferase reporter assay. Since the expression of DDX3X is affected by the activity of HIF1A, the co-localization of these proteins has also been demonstrated in MDA-MB-231 xenograft tumor samples.[10]

In HeLa cells DDX3X is reported to control cell cycle progression through Cyclin E1.[11] More specifically, DDX3X was shown to directly bind to the 5´ UTR of Cyclin E1 and thereby facilitating the translation of the protein. Increased protein levels of Cyclin E1 was demonstrated to mediate the transition of S phase entry.[11]

Melanoma survival, migration and proliferation is affected by DDX3X activity.[12] Melanoma cells with low DDX3X expression exhibit a high migratory capacity, low proliferation rate and reduced vemurafenib sensitivity. While high DDX3X expressing cells are drug sensitive, more proliferative and less migratory. These phenotypes can be explained by the translational effects on the melanoma transcription factor MITF.[12] The 5' UTR of the MITF mRNA contains a complex RNA regulon (IRES) that is bound and activated by DDX3X. Activation of the IRES leads to translation of the MITF mRNA. Mice injected with melanoma cells with a deleted IRES display more aggressive tumor progression including increased lung metastasis.[12] Interestingly, the DDX3X in melanoma is affected by vemurafenib via an undiscovered mechanism. It is unknown how DDX3X is downregulated by the presence of vemurafenib. However, reduced levels of DDX3X during drug treatment explains the development of drug resistant cells frequently detected with low MITF expression.[12][13][14]

Clinical significance

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Mutations of the DDX3X gene are associated with medulloblastoma.[15][16][17] In melanoma the low expression of the gene is linked to a poor distant metastasis free survival.[12] In addition, the mRNA level of DDX3X is lower in matched post-relapse melanoma biopsies for patients receiving vemurafenib and in progressing tumors.

Mutations of the DDX3X gene also cause DDX3X syndrome, which affects predominantly females and presents with developmental delay or disability, autism, ADHD, and low muscle tone.

See also

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References

[edit]
  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000215301 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000000787 – Ensembl, May 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. ^ Lahn BT, Page DC (October 1997). "Functional coherence of the human Y chromosome". Science. 278 (5338): 675–80. Bibcode:1997Sci...278..675L. doi:10.1126/science.278.5338.675. PMID 9381176.
  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. S2CID 46774908.
  7. ^ a b "Entrez Gene: DDX3X DEAD (Asp-Glu-Ala-Asp) box polypeptide 3, X-linked".
  8. ^ Yedavalli VS, Neuveut C, Chi YH, Kleiman L, Jeang KT (October 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.
  9. ^ Heaton SM, Atkinson SC, Sweeney MN, Yang SN, Jans DA, Borg NA (September 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. PMC 6848931. PMID 31575075.
  10. ^ a b c Botlagunta M, Krishnamachary B, Vesuna F, Winnard PT, Bol GM, Patel AH, et al. (March 2011). "Expression of DDX3 is directly modulated by hypoxia inducible factor-1 alpha in breast epithelial cells". PLOS ONE. 6 (3): e17563. Bibcode:2011PLoSO...617563B. doi:10.1371/journal.pone.0017563. PMC 3063174. PMID 21448281.
  11. ^ a b Lai MC, Chang WC, Shieh SY, Tarn WY (November 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.
  12. ^ a b c d e Phung B, Cieśla M, Sanna A, Guzzi N, Beneventi G, Cao Thi Ngoc P, et al. (June 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. (December 2014). "Low MITF/AXL ratio predicts early resistance to multiple targeted drugs in melanoma". Nature Communications. 5 (1): 5712. Bibcode:2014NatCo...5.5712M. doi:10.1038/ncomms6712. PMC 4428333. PMID 25502142.
  14. ^ Konieczkowski DJ, Johannessen CM, Abudayyeh O, Kim JW, Cooper ZA, Piris A, et al. (July 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. Bibcode:2012Natur.488...43R. 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. Bibcode:2012Natur.488..100J. 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. Bibcode:2012Natur.488..106P. doi:10.1038/nature11329. PMC 3413789. PMID 22820256.

Further reading

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