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The role of TALE transcription factors in the retinoic acid induced activation of SOX3 gene

dc.contributor.advisorStevanović, Milena
dc.contributor.otherRadović, Svetlana
dc.contributor.otherBrajušković, Goran
dc.creatorMojsin, Marija
dc.date.accessioned2019-05-16T10:19:23Z
dc.date.available2019-05-16T10:19:23Z
dc.date.available2020-07-03T08:07:44Z
dc.date.issued2008
dc.identifier.urihttp://nardus.mpn.gov.rs/handle/123456789/11025
dc.identifier.urihttp://eteze.bg.ac.rs/application/showtheses?thesesId=6755
dc.identifier.urihttps://fedorabg.bg.ac.rs/fedora/get/o:19621/bdef:Content/download
dc.identifier.urihttp://vbs.rs/scripts/cobiss?command=DISPLAY&base=70036&RID=34659855
dc.description.abstractSox3/SOX3 gen je jedan od najranijih markera neuralnog razvića kičmenjaka, koji ima ključnu ulogu u održavanju populacije ćelija neuralnih progenitora. Naša ranija istraživanja dovela su do prve karakterizacije promotora humanog SOX3 gena i identifikacije kontrolnih elemenata preko kojih su opšti transkripcioni faktori NF-Y, Sp1 i USF uključeni u regulaciju ekspresije ovog gena. Rezultati predstavljeni u ovom radu po prvi put pokazuju da su TALE transkripcioni faktori PBX1, MEIS1 i TGIF uključeni u regulaciju ekspresije humanog SOX3 gena. PBX1 i MEIS1 proteini direktno interaguju sa konsenzusnim mestom za vezivanje Pbx/Meis heterodimera koje je visoko evolutivno očuvano u bazalnom promotoru Sox3 gena sisara. PBX1 je prisutan u proteinskim kompleksima formiranim na ovom mestu sa jedarnim proteinima iz neindukovanih ćelija, dok su i PBX1 i MEIS1 prisutni u kompleksima formiranim sa jedarnim proteinima iz NT2/D1 ćelija indukovanih retinoičnom kiselinom. Zanimljivo je da je MEIS1 jedini do sada identifikovani faktor koji interaguje sa kontrolnim elementima SOX3 promotora tek nakon indukcije ovog gena retinoičnom kiselinom. Funkcionalne analize su pokazale da mutacije Pbx/Meis vezivnog mesta dovode do pada aktivnosti SOX3 promotora u RA indukovanim NT2/D1 ćelijama, dok povećana ekspresija PBX1 i MEIS1 proteina dovodi do aktivacije SOX3 gena kako u indukovananim tako i u neindukovanim ćelijama. Transkripcioni faktor TGIF ostvaruje funkciju transkripcionog represora interakcijom sa konsenzusnim vezivnim mestom u promotoru SOX3 gena. Mutacija ovog mesta dovodi do povećane aktivnosti SOX3 promotora, dok povećana ekspresija transkripcionog faktora TGIF značajno smanjuje ekspresiju SOX3 gena u neindukovanim i RA indukovanim NT2/D1 ćelijama. Prikazani rezultati po prvi put uspostavljaju funkcionalnu vezu izmedu članova TALE familije transkripcionih faktora (PBX1, MEIS1 i TGIF) i ekspresije humanog SOX3 gena. Povezivanje ove dve familije trankripcionih faktora ima poseban značaj kada se ima u vidu njihova uloga tokom razvića nervnog sistema kičmenjaka.sr
dc.description.abstractSox3/SOX3 is considered to be one of the earliest neural markers in vertebrates, playing the role in specifying neuronal fate. The characterization of SOX3 promoter was previously reported and it was demonstrated that general transcription factors NF-Y, and USF are involved in transcriptional regulation of the SOX3 promoter. In this thesis first evidence is presented that TALE transcription factors PBX1, MEIS1 and TGIF are involved in the regulation of human SOX3 gene expression. PBX1 and MEIS1 proteins are involved in the up-regulation of human SOX3 gene expression in NT2O1 cells by direct interaction with the consensus Pbx/Meis binding site that is conserved in all analyzed mammalian orthologue promoters. PBX1 is present in the protein complex formed on this site with nuclear proteins from uninduced cells, while both, PBX1 and MEIS1 proteins were detected in the complex created with extract from retinoic acid (RA) induced NT2/D1 cells. Interestingly, MEIS1 is the only transcription factor demonstrated so far to interact with SOX3 promoter upon RA induced activation of the SOX3 gene expression. By functional analysis it was demonstrated that mutations of the Pbx1/Meis1 binding sites resulted in profound reduction of the SOX3 promoter responsiveness to RA. Finally, it was demonstrated that overexpressed Pbx1 and Mets1 increased endogenous SOX3 protein expression in both uninduced and RA induced NT2/D1 cells. Transcription factor TGIF is involved in the down-regulation of human SOX3 gene by direct interaction with the binding site within SOX3 promoter. Functional analysis showed that mutation of the TGIF binding site increased SOX3 expression while overexpressed TGIF decreased SOX3 expression in both uninduced and RA induced NT2/D1 cells. By data presented here, for the first time, a functional link was established between TALE proteins, PBX1, MEIS1 and TGIF and expression of human SOX3 gene. This link is of particular interest since both TALE family members and members of SOX super-family are recognized as important developmental regulators.en
dc.formatapplication/pdf
dc.languagesr
dc.publisherУниверзитет у Београду, Биолошки факултетsr
dc.rightsopenAccessen
dc.sourceУниверзитет у Београдуsr
dc.subjectNT2/D1 ćelijesr
dc.subjectNT2/D1 cellsen
dc.subjectSOX3en
dc.subjectPBX1en
dc.subjectMEIS1en
dc.subjectTGIFen
dc.subjectretinoic aciden
dc.subjectSOX3sr
dc.subjectPBX1sr
dc.subjectMEIS1sr
dc.subjectTGIFsr
dc.subjectretinoična kiselinasr
dc.titleUloga TALE transkripcionih faktora u regulaciji ekspresije SOX3 gena retinoičnom kiselinomsr
dc.title.alternativeThe role of TALE transcription factors in the retinoic acid induced activation of SOX3 geneen
dc.typedoctoralThesis
dc.rights.licenseBY-NC-ND


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