GATA3 Identifikatori Aliasi GATA3 Vanjski ID-jevi OMIM : 131320 MGI : 95663 HomoloGene : 1550 GeneCards : GATA3 Ontologija gena Molekularna funkcija • RNA polymerase II transcription regulatory region sequence-specific DNA binding • HMG box domain binding • chromatin binding • vezivanje iona metala • vezivanje sa DNK • GO:0001158 cis-regulatory region sequence-specific DNA binding • sequence-specific DNA binding • GO:0001077, GO:0001212, GO:0001213, GO:0001211, GO:0001205 DNA-binding transcription activator activity, RNA polymerase II-specific • GO:0001078, GO:0001214, GO:0001206 DNA-binding transcription repressor activity, RNA polymerase II-specific • interleukin-2 receptor binding • core promoter sequence-specific DNA binding • GO:0000975 transcription cis-regulatory region binding • protein dimerization activity • E-box binding • GO:0001948, GO:0016582 vezivanje za proteine • vezivanje iona cinka • transcription factor binding • GO:0001105 transcription coactivator activity • GO:0000980 RNA polymerase II cis-regulatory region sequence-specific DNA binding • GO:0001131, GO:0001151, GO:0001130, GO:0001204 DNA-binding transcription factor activity • GO:0001200, GO:0001133, GO:0001201 DNA-binding transcription factor activity, RNA polymerase II-specific • GO:0001104 transcription coregulator activity Ćelijska komponenta • jedro • transcription regulator complex • nukleoplazma Biološki proces • negative regulation of cell population proliferation • regulation of establishment of cell polarity • ureteric bud formation • negative regulation of cell cycle • thymic T cell selection • response to ethanol • positive regulation of T cell differentiation • erythrocyte differentiation • inner ear morphogenesis • cell maturation • regulation of histone H3-K27 methylation • cardiac right ventricle morphogenesis • phosphatidylinositol 3-kinase signaling • norepinephrine biosynthetic process • ear development • homeostasis of number of cells • sympathetic nervous system development • T-helper 2 cell differentiation • regulation of cellular response to X-ray • cell fate determination • post-embryonic development • cellular response to BMP stimulus • mesonephros development • neuron differentiation • regulation of neuron apoptotic process • GO:0072468 Transdukcija signala • cellular response to cytokine stimulus • cellular response to interleukin-4 • T cell receptor signaling pathway • neuron migration • positive regulation of interleukin-5 production • regulation of CD4-positive, alpha-beta T cell differentiation • parathyroid gland development • negative regulation of DNA demethylation • positive regulation of interleukin-4 production • negative regulation of mammary gland epithelial cell proliferation • GO:0044324, GO:0003256, GO:1901213, GO:0046019, GO:0046020, GO:1900094, GO:0061216, GO:0060994, GO:1902064, GO:0003258, GO:0072212 regulation of transcription by RNA polymerase II • thymus development • nervous system development • otic vesicle development • GO:0009373 regulation of transcription, DNA-templated • positive regulation of T-helper 2 cell cytokine production • regulation of nephron tubule epithelial cell differentiation • positive regulation of thyroid hormone generation • lymphocyte migration • negative regulation of interleukin-2 production • regulation of neuron projection development • uterus development • axon guidance • mesenchymal to epithelial transition • negative regulation of cell proliferation involved in mesonephros development • aortic valve morphogenesis • cellular response to tumor necrosis factor • negative regulation of fat cell differentiation • anatomical structure morphogenesis • cellular response to interferon-alpha • GO:0045996 negative regulation of transcription, DNA-templated • T cell differentiation • response to virus • negative regulation of endothelial cell apoptotic process • Urođeni imunski sistem • canonical Wnt signaling pathway involved in metanephric kidney development • positive regulation of transcription regulatory region DNA binding • positive regulation of endothelial cell migration • positive regulation of interleukin-13 production • in utero embryonic development • negative regulation of interferon-gamma production • humoral immune response • developmental growth • Nefrogeneza • positive regulation of ureteric bud formation • GO:1901313 positive regulation of gene expression • mast cell differentiation • positive regulation of histone H3-K9 acetylation • positive regulation of cell differentiation • GO:1901227 negative regulation of transcription by RNA polymerase II • male gonad development • nephric duct morphogenesis • ventricular septum development • GO:0032737 positive regulation of cytokine production • lens development in camera-type eye • negative regulation of fibroblast growth factor receptor signaling pathway involved in ureteric bud formation • transcription, DNA-templated • negative regulation of gene expression • parathyroid hormone secretion • nephric duct formation • immune system process • negative regulation of inflammatory response • pharyngeal system development • embryonic organ development • response to estrogen • Koagulacija (krv) • negative regulation of glial cell-derived neurotrophic factor receptor signaling pathway involved in ureteric bud formation • positive regulation of signal transduction • ureter maturation • positive regulation of histone H3-K14 acetylation • GO:0060469, GO:0009371 positive regulation of transcription, DNA-templated • response to gamma radiation • GO:0000767 cell morphogenesis • embryonic hemopoiesis • GO:0003257, GO:0010735, GO:1901228, GO:1900622, GO:1904488 positive regulation of transcription by RNA polymerase II • negative regulation of cell motility • pro-T cell differentiation • TOR signaling • type IV hypersensitivity • defense response • regulation of histone H3-K4 methylation • renal system development • positive regulation of protein kinase B signaling • cell activation • chromatin remodeling • T cell differentiation in thymus • cochlea development • transcription by RNA polymerase II • protein deubiquitination • anatomical structure formation involved in morphogenesis • regulation of hematopoietic stem cell differentiation • cytokine-mediated signaling pathway • heart development • animal organ morphogenesis • tissue development • cell development • digestive tract development • immune system development • regulation of epithelial cell differentiation • ureter morphogenesis Izvori:Amigo / QuickGO
Ortolozi Vrste Čovjek Miš Entrez Ensembl UniProt RefSeq (mRNK) RefSeq (bjelančevina) Lokacija (UCSC) Chr 10: 8.05 – 8.08 Mb Chr 2: 9.86 – 9.89 Mb PubMed pretraga[ 3] [ 4] Wikipodaci
GATA3 je transkripcijski faktor koji je kod ljudi kodiran genom GATA3 . Studije na životinjskim modelima i ljudima pokazuju da kontrolira ekspresiju širokog spektra biološki i klinički važnih gena.[ 5] [ 6] [ 7]
Transkripcijski faktor GATA3 kritičan je za embrionski razvoj različitih tkiva, kao i za upalnu i humoralnu imunsku reakciju i pravilno funkcioniranje endotela krvnih sudova . GATA3 ima centralnu ulogu u alergijama i imunosti protiv infekcija glistama.[ 8] [ 9] Haploinsuficiencija GATA3 (tj. gubitak jednog ili dva naslijeđena gena GATA3 ) rezultira kongenitalnim poremećajem koji se naziva Barakatov sindrom .[ 10] [ 11] [ 12]
Sadašnja klinička i laboratorijska istraživanja usredotočena su na utvrđivanje prednosti izravnog ili neizravnog blokiranja djelovanja GATA3 kod upalnih i alergijskih bolesti, ko što je astma . Također se predlaže da bude klinički važan marker za različite tipove raka, posebno one raka dojke . Međutim, ako postoji, uloga GATA3 u razvoju ovih karcinoma se proučava i ostaje nejasna.[ 13]
Dužina polipeptidnog lanca je 443 aminokiseline , а molekulska težina 47 916 Da .[ 14]
10 20 30 40 50
MEVTADQPRW VSHHHPAVLN GQHPDTHHPG LSHSYMDAAQ YPLPEEVDVL
FNIDGQGNHV PPYYGNSVRA TVQRYPPTHH GSQVCRPPLL HGSLPWLDGG
KALGSHHTAS PWNLSPFSKT SIHHGSPGPL SVYPPASSSS LSGGHASPHL
FTFPPTPPKD VSPDPSLSTP GSAGSARQDE KECLKYQVPL PDSMKLESSH
SRGSMTALGG ASSSTHHPIT TYPPYVPEYS SGLFPPSSLL GGSPTGFGCK
SRPKARSSTG RECVNCGATS TPLWRRDGTG HYLCNACGLY HKMNGQNRPL
IKPKRRLSAA RRAGTSCANC QTTTTTLWRR NANGDPVCNA CGLYYKLHNI
NRPLTMKKEG IQTRNRKMSS KSKKCKKVHD SLEDFPKNSS FNPAALSRHM
SSLSHISPFS HSSHMLTTPT PMHPPSSLSF GPHHPSSMVT AMG
Gen GATA3 nalazi se blizu kraja kratkog kraka hromosoma 10, na poziciji p14. Sastoji se od osam egzona i kodira dvije varijante; varijanta 1 i GATA3, varijanta 2.[ 15] Ekspresija GATA3 može biti djelimično reguliranaregulated in part or putem antisens RNK , GATA3-AS1, čiji geni su locirani u blizini genaGATA3 , na kratkom kraku hromosoma 10, pozicija p14.[ 16] Različiti tipovi mutacija uključujući tačkaste mutacije kao i male i velike delecijske mutacije uzrokuju autosomno dominantni genetički poremećaj , Barakatov sindrom (koji se naziva i hipoparatiroidizam, gluhoća i sindrom bubrežne displazije). Lokus GATA3 graniči s drugim kritičnim mjestima na hromosomu 10, posebno lokacijom koja se nalazi na 10p14-p13. Mutacije na ovom mjestu uzrokuju urođeni poremećaj DiGeorgeov sindrom /kompleks 2 velokardiofacijalnog sindroma (ili DiGeorgeov sindrom 2).[ 17] Velikoskalirane delecije u GATA3 mogu se proširiti na područje DiGeorge sindroma 2 i na taj način uzrokovati složeni sindrom sa obilježjima Barakatovog sindroma u kombinaciji s nekim od onih iz DiGeorgeovog sindroma 2.[ 12] [ 18] Nokaut oba gena GATA3 kod miševa je fatalan: ove životinje umiru u embrionskim danima 11 i 12, zbog unutrašnjeg krvarenja . Također pokazuju velike deformitete u mozgu i kičmi, kao i aberacije u jetrenoj hematopoezi fetusa .[ 19]
GATA3 varijanta 1 je linearni protein koji se sastoji od 444 aminokiseline . Proteinska GATA3 varijanta 2 je identično strukturirana izoforma , ali je kraća za jednu aminokiselinu od GATA3 varijante 1. Razlike, ako ih ima, u funkcijama ove dvije varijante nisu prijavljene.[ 20] varijanta 2, iRNK. Što se tiče najbolje proučene varijante, varijanta 1, ali vjerovatno i varijanta 2 , jedan od strukturnih motiva cinkovog prsta , ZNF2, nalazi se na C-kraju proteina i veže se za specifične promotore gena . Sekvence DNK reguliraju ekspresiju gena koje kontroliraju ovi promotori. Drugi cinkov prst, ZNF1, nalazi se na proteinskom N-terminalu i stupa u interakciju s različitim jedarnim faktorima, uključujući protein cinkovog prsta 1 (tj. ZFPM1, koji se također naziva šaperonom GATA1 (tj. FOG-1) i ZFPM2 (tj. FOG-2), koji moduliraju djelovanje GATA3 gena za stimulaciju.[ 21]
Transkripcijski faktor GATA3 regulira ekspresiju gena uključenih u razvoj različitih tkiva, kao i gena uključenih u fiziološke kao i patološke humoralne upalne i alergijske reakcije.[ 10] [ 12]
GATA3 pripada porodici GATA faktora transkripcije . Studije delecije gena na miševima. pokazuju da je Gata3 (gen miša ekvivalentan GATA3) kritičan za embrionski razvoj i/ili funkciju različitih tipova ćelija (npr. mast ćelije , ćelije nervog grebena , limfociti ) i tkiva više organa (npr. bubreg , jetra , mozak , kičmena moždina , mliječne žlijezde ).[ 11] Studije na ljudima implicira GATA3 na sljedeće:
GATA3 je potreban za razvoj paratiroidne žlijezde , senzornih komponenti slušnog sistema i bubrega kod životinja i ljudi.[ 12] Može se takođe doprinose razvoju vagine i materice kod ljudi.[ 22]
Kod ljudi, GATA3 je potreban za razvoj i/ili funkciju urođenih limfoidnih ćelija (ILC), posebno ILC grupe 2 , kao i za razvoj T pomoćnih ćelija , (Th ćelije), posebno Th2 ćelija. ILC grupe 2 i Th2 ćelije, a time i GATA3, kritični su za razvoj alergijskih i humoralnoimunskog odgovora kod ljudi. Uporedne studije na životinjama ukazuju na da GATA3 utiče na razvoj limfocita koji posreduju u alergijskoj i humoralnoi imunosti, kao i u alergijskim i humoralnim imunskim odgovorima .[ 22] [ 23]
GATA3 podstiče lučenje IL-4 , IL-5 i IL-13 iz Th2 ćelija kod ljudi i ima slična djelovanja na slične mišje limfocite. Sva tri ova interleukina služe za podsticanje alergijske reakcije,[ 24]
GATA3 inducira sazrijevanje prekursornih epitelneih ćelija dojke i održava ih u zrelom stanju kod miševa i vjerovatno ljudi.[ 25] [ 26]
Kod miševa, GATA3 je odgovoran za normalan razvoj različitih tkiva, uključujući kožu , mastocite , timus i nervni sistem .[ 22] [ 27]
Inaktiviranje mutacija u jednom od dva roditeljska gena GATA3 uzrokuje kongenitalni poremećaj hipoparatiroidizam sa senzorinervnom gluhoćom i bubrežnim malformacijama , tj. Barakatovim sindromom . Ovaj rijetki sindrom može se pojaviti u porodicama ili kao nova mutacija kod osoba iz porodice bez historije poremećaja. Mutacije u GATA3 uzrokuju različite stupnjeve hipoparatiroidizma, gluhoće i urođene mahane bolesti bubrega zbog
Individualnih razlika u penetraciji mutacije,
sporadična, i još uvijek nerazjašnjena, povezanost s malformacijama maternice i vagine, i *mutacije koje se protežu izvan gena GATA3 u hromosomska područja gdje su mutacije odgovorne za razvoj drugih tipova abnormalnosti koje su karakteristike DeGeorgeovog sindroma 2. Barakatov sindrom nastaje zbog haploinsuficijencija u nivoima GATA3, odnosno nivoa transkripcijskih faktora koji su nedovoljni za normalan razvoj pomenutih tkiva tokom embriogeneze .[ 11] [ 12] [ 18]
Studije na miševima pokazuju da inhibiranje ekspresije GATA3 metodima antisens RNK potiskuje alergijsku upalu. Protein je nadeksprimiran u zahvaćenim tkivima osoba s različitim oblicima alergija, uključujući astmu, rinitis, nosne polipe i atopijski ekcem. To sugerira da bi on mogao imati ulogu u podsticanju ovih poremećaja.[ 28] U fazi IIA kliničkih ispitivanja studija osoba koji pate od astme uzrokovane alergenima, inhalacija dezoksiribozimom ST010, koja specifično inaktivira GATA3 iRNK , smanjena je za 28 dana rani i kasni imunski odgovor pluća na inhalacijski alergen. Smatra se da je klinička korist inhibicije GATA3 u ovom poremećaju posljedica ometanja funkcije ILC-a Grupe 2 i Th2-ćelija, naprimjer, smanjenjem proizvodnje IL-4, IL-13, a posebno IL-5. Smatra se da smanjenje ovih eozinofilno -stimulirajućih interleukina, smanjuje sposobnost ovih ćelija da podstiču alergijsku reaktivnost i reakcije.[ 10] [ 29] Iz sličnih razloga, liječenje bi se također moglo pokazati klinički korisnim za liječenje drugih alergijskih poremećaja.[ 28]
GATA3 je jedan od tri mutirana gena u > 10% slučajeva raka dojke (Cancer Genome Atlas).[ 30] Studije na miševima pokazuju da je gen kritičan za normalan razvoj tkiva dojke i izravno regulira diferencijaciju lumenskih ćelija (tj. ćelijaa koje oblažu mliječne kanale) u eksperimentalno induciranom karcinomu dojke.[ 19] [ 31] Analize ljudskog tkiva raka dojke ukazuju da je GATA3 potreban za specifični tip raka dojke niskog rizika (tj. lumenski A), sastavni je dio ekspresije receptora estrogena alfa i (kod receptora estrogena negativnih/pozitivnih karcinoma receptora androgena) signalizacija androgenih receptora .[ 32] [ 33] [ 34] Ove studije sugeriraju da je "GATA3" uključen u razvoj barem određenih tipova raka dojke kod ljudi. Međutim, postoji neslaganje oko toga, a neke studije sugeriraju da ekspresija "GATA3" djeluje tako da inhibira, a druge studije sugeriraju da djeluje na podsticanje razvoja, rasta i/ili širenja ovog raka. Potrebne su daljnje studije kako bi se razjasnila uloga, ako postoji, GATA3 u razvoju raka dojke.[ 19]
Imuocitokemijska analiza proteina GATA3 u ćelijama dojke vrijedan je marker za dijagnosticiranje primarnog karcinoma dojke, testiran je kao pozitivan u do 94% slučajeva. Posebno je vrijedan za karcinom dojke pozitivan na estrogene receptore, ali je manje osjetljiv (43,5-66% povišen), iako je još uvijek vrijedniji od mnogih drugih markera za dijagnosticiranje trostruko negativnog raka dojke . Ova analiza se naširoko koristi kao klinički vrijedan marker raka dojke.[ 35] [ 36]
Slično tumorima dojke, uloga GATA3 u genezi drugih tipova tumora nije jasna, ali otkrivanje proizvoda njegovog transkripcijskog faktora može biti dijagnostički korisno. Imuocitohemijska analiza proteina GATA3 smatra se vrijednim markerom za određene vrste raka mokraćnog mjehura i raka mokraćovoda , kao i za tumore paratiroidne žlijezde (kancerogene ili benigne). Za pojedinačne serije izvještaji sugeriraju da bi ova analiza mogla biti od koristi i za dijagnosticiranje tumora pljuvačnih žlijezda , karcinom pljuvačnih kanala , analognog sekretornog karcinoma dojke , benignih tuomra jajnika Brenerovih tumora , benignih Walthardovih ćelija i paraganglioma .[ 13] [ 37]
Pokazalo se da GATA3 stupa u interakciju sa sljedećim regulatorima transkripcijskih faktora : ZFPM1 i ZFPM2 ;[ 21] LMO1 ;[ 38] [ 39] i FOXA1 .[ 40] Ovi regulatori mogu promovirati ili inhibirati GATA3 u podsticanju ekspresije njegovih ciljnih gena .
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^ Zhu J (2017). "GATA3 Regulates the Development and Functions of Innate Lymphoid Cell Subsets at Multiple Stages" . Frontiers in Immunology . 8 : 1571. doi :10.3389/fimmu.2017.01571 . PMC 5694433 . PMID 29184556 .
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(1) Basic domains
(1.1) Osnovni leucine zipper (bZIP )(1.2) Basic helix-loop-helix (bHLH )
Group A Group B Grupa C bHLH-PAS Grupa D Grupa E Grupa F bHLH-COE
(1.3) bHLH-ZIP (1.4) NF-1 (1.5) RF-X (1.6) Basic helix-span-helix (bHSH)
(2) Cinkov prst DNA-binding domains
(2.1) Nuclear receptor (Cys4 )
potporodica 1 potporodica 2 potporodica 3 potporodica 4 potporodica 5 potporodica 6 potporodica 0
(2.2) Other Cys4 (2.3) Cys2 His2 (2.4) Cys6 (2.5) Alternating composition (2.6) WRKY
(4) β-Scaffold factors with minor groove contacts
(0) Other transcription factors