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TBX3

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TBX3
Dostupne strukture
PDBPretraga ortologa: PDBe RCSB
Spisak PDB ID kodova

1H6F

Identifikatori
AliasiTBX3
Vanjski ID-jeviOMIM: 601621 MGI: 98495 HomoloGene: 4371 GeneCards: TBX3
Lokacija gena (čovjek)
Hromosom 12 (čovjek)
Hrom.Hromosom 12 (čovjek)[1]
Hromosom 12 (čovjek)
Genomska lokacija za TBX3
Genomska lokacija za TBX3
Bend12q24.21Početak114,670,255 bp[1]
Kraj114,684,175 bp[1]
Lokacija gena (miš)
Hromosom 5 (miš)
Hrom.Hromosom 5 (miš)[2]
Hromosom 5 (miš)
Genomska lokacija za TBX3
Genomska lokacija za TBX3
Bend5 F|5 60.34 cMPočetak119,808,734 bp[2]
Kraj119,822,789 bp[2]
Obrazac RNK ekspresije
Više referentnih podataka o ekspresiji
Ontologija gena
Molekularna funkcija GO:0001078, GO:0001214, GO:0001206 DNA-binding transcription repressor activity, RNA polymerase II-specific
sequence-specific DNA binding
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
vezivanje sa DNK
GO:0001948, GO:0016582 vezivanje za proteine
GO:0001200, GO:0001133, GO:0001201 DNA-binding transcription factor activity, RNA polymerase II-specific
Ćelijska komponenta jedro
Biološki proces forelimb morphogenesis
Ćelijsko starenje
branching involved in mammary gland duct morphogenesis
positive regulation of stem cell proliferation
atrioventricular bundle cell differentiation
negative regulation of epithelial cell differentiation
female genitalia development
transcription, DNA-templated
male genitalia development
multicellular organism development
anterior/posterior axis specification, embryo
outflow tract morphogenesis
skeletal system development
ventricular septum morphogenesis
embryonic forelimb morphogenesis
cardiac muscle cell fate commitment
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
heart morphogenesis
regulation of cell population proliferation
heart looping
negative regulation of myoblast differentiation
specification of animal organ position
stem cell population maintenance
luteinizing hormone secretion
follicle-stimulating hormone secretion
blood vessel development
positive regulation of cell population proliferation
GO:0060469, GO:0009371 positive regulation of transcription, DNA-templated
roof of mouth development
mammary placode formation
in utero embryonic development
mesoderm morphogenesis
GO:0009373 regulation of transcription, DNA-templated
limb morphogenesis
sinoatrial node cell development
positive regulation of cell cycle
cardiac muscle cell differentiation
limbic system development
embryonic hindlimb morphogenesis
animal organ morphogenesis
embryonic heart tube development
embryonic digit morphogenesis
mammary gland development
GO:1901227 negative regulation of transcription by RNA polymerase II
GO:0045996 negative regulation of transcription, DNA-templated
negative regulation of apoptotic process
Izvori:Amigo / QuickGO
Ortolozi
VrsteČovjekMiš
Entrez
Ensembl
UniProt
RefSeq (mRNK)

NM_016569
NM_005996

NM_011535
NM_198052

RefSeq (bjelančevina)

NP_005987
NP_057653

NP_035665
NP_932169

Lokacija (UCSC)Chr 12: 114.67 – 114.68 MbChr 5: 119.81 – 119.82 Mb
PubMed pretraga[3][4]
Wikipodaci
Pogledaj/uredi – čovjekPogledaj/uredi – miš

T-boksni transkripcijski faktor TBX3 jest protein koji je kod ljudi kodiran genom TBX3.[5][6]

T-boks 3 (TBX3) je član porodice gena T-kutije transkripcijskih faktora koji svi dijele visoko konzervirani domen vezanja za DNK poznat kao T-kutija. Porodica gena ove kutije sastoji se od 17 članova kod miševa i ljudi, koji su grupirani u pet potporodica, i to Brachyury (T), T-moždana (Tbr1), TBX1, TBX2 i TBX6. Tbx3 je član potporodice Tbx2 koja uključuje Tbx2, Tbx4 i Tbx5.[7] Ljudski gen TBX3 nalazi se u hromosomu 12, na poziciji 12q23-24.1 i sastoji se od sedam egzon koji kodiraju protein od 723 aminokiseline (prema ENSEMBL, sklop GRCh38.p12).

Prerada transkripta

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Alternativna prerada trankripta rezultira u najmanje četiri različita TBX3 izoforme s TBX3 i TBX3+2a kao dominantnim izoformama. TBX3 +2a je rezultat alternativne prerade drugog introna, što dovodi do dodavanja +2a egzona, pa prema tome ova izoforma ima dodatnih 20 aminokiselina unutar domena vezanja T-kutije DNK.[8][9] Funkcije TBX3 i TBX3+2a mogu se malo razlikovati kod različitih tipova ćelija.[9][10][11][12][13][14]

Aminokiselinska sekvenca

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Dužina polipeptidnog lanca je 743 aminokiseline, a molekulska težina 79.389 Da.[15]

1020304050
MSLSMRDPVIPGTSMAYHPFLPHRAPDFAMSAVLGHQPPFFPALTLPPNG
AAALSLPGALAKPIMDQLVGAAETGIPFSSLGPQAHLRPLKTMEPEEEVE
DDPKVHLEAKELWDQFHKRGTEMVITKSGRRMFPPFKVRCSGLDKKAKYI
LLMDIIAADDCRYKFHNSRWMVAGKADPEMPKRMYIHPDSPATGEQWMSK
VVTFHKLKLTNNISDKHGFTLAFPSDHATWQGNYSFGTQTILNSMHKYQP
RFHIVRANDILKLPYSTFRTYLFPETEFIAVTAYQNDKITQLKIDNNPFA
KGFRDTGNGRREKRKQLTLQSMRVFDERHKKENGTSDESSSEQAAFNCFA
QASSPAASTVGTSNLKDLCPSEGESDAEAESKEEHGPEACDAAKISTTTS
EEPCRDKGSPAVKAHLFAAERPRDSGRLDKASPDSRHSPATISSSTRGLG
AEERRSPVREGTAPAKVEEARALPGKEAFAPLTVQTDAAAAHLAQGPLPG
LGFAPGLAGQQFFNGHPLFLHPSQFAMGGAFSSMAAAGMGPLLATVSGAS
TGVSGLDSTAMASAAAAQGLSGASAATLPFHLQQHVLASQGLAMSPFGSL
FPYPYTYMAAAAAASSAAASSSVHRHPFLNLNTMRPRLRYSPYSIPVPVP
DGSSLLTTALPSMAAAAGPLDGKVAALAASPASVAVDSGSELNSRSSTLS
SSSMSLSPKLCAEKEAATSELQSIQRLVSGLEAKPDRSRSASP
Simboli

Struktura i funkcija

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TBX3 ima domene koji su važni za njegovu funkciju transkripcijskog faktora, a koje uključuju domen koja se veže za DNK (DBD), zvami i T-box, signal nuklearne lokalizacije, dva domena represije (R2 i R1) i aktivacijsko područje (A).[16] T-okvir prepoznaje palindromsku DNK-sekvencu (T (G/C) ACACCT AGGTGTGAAATT) poznatu kao T-element, ili pola mjesta unutar ove sekvence koja se naziva pola T-elemenata, iako može prepoznati i varijacije unutar konsenzusnih sekvenci T-elemenata. Iako postoji 29 predviđenih mjesta fosforilacija u proteinu TBX3, samo su SP190, SP692 i S720 u potpunosti okarakterizirani. Uključene kinaze su ciklin A-CDK2 na SP190 ili SP354, p38 mitogen-aktivirani protein (MAP) kinaza na SP692 u embrionskim ćelijama bubrega i AKT3 na S720 kod melanoma. Ove izmjene djeluju na konteksto zavisan način i promiču stabilnost proteina TBX3, jedarnu lokalizaciju i transkripcijsku aktivnost.[17][18]

TBX3 može aktivirati i/ili potisnuti svoje ciljne gene vezivanjem T-elementa ili polovine T-elemenata.[19] Zaista, Tbx3 veže visoko konzervirane T-elemente za aktiviranje promotora Eomes, T, Sox17 i Gata6, koji su bitni faktori za diferencijaciju mezoderma i vanembrionskog endoderma.[20][21] Nadalje, u kontekstu raka, TBX3 direktno potiskuje regulatore ćelijskog ciklusa p19ARF/p14ARF,[22] p21WAF1 [23] i TBX2 [24] kao i E-kadherin, koji kodira ćelijsku adhezijsku molekulu, za podstcanje proliferacije i migracije. TBX3 izravno potiskuje područje promotora PTEN kojem nedostaju navodni T-elementi, ali koji čini važnu regulatornu jedinicu za PTEN-ove transkripcijske aktivatore, čime se povećava mogućnost da TBX3 može također potisnuti neke svoje ciljne gene ometajući transkripcijske aktivatore.[25]

Funkcija TBX3 ili kao transkripcijskog represora ili transkripcijskog aktivatora, djelimično je modulirana proteinskim kofaktorima. Naprimjer, može stupiti u interakciju s drugim faktorima transkripcije, poput Nkx2-5, Msx 1/2[26] i Sox4[27] to assist it binding to its target genes to regulate heart development [10][28][29][30][31] i može stupiti u interakciju s histon-deacetilazima (HDACs) 1, 2, 3 i 5, kako bi potisnuo p14ARF u karcinomu dojke i s HDAC5, kako bi supresirao E-kadherin za podsticanje metastaza u hepatoćelijskom karcinomu.[32][33] Na kraju, TBX3 može također surađivati s drugim faktorima kako bi inhibirao proces prerade iRNK direktnim vezanjem RNK koje sadrže jezgro motiva T-elementa. Zaista, TBX3 stupa u interakciju s koaktivatorom AP1 i receptorom estrogena (CAPERα), kako bi potisnuo dugolančanu nekodirajuću RNK, urotelijski karcinom povezan 1 (UCA1), koji dovodi do zaobilaženja starenja, stabilizacijom p16INK4a iRNK.[34]

Klinički značaj

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TBX3 je uključen u ljudske bolesti, uključujući sindrom ulnusne dojke,[35] gojaznost,[36] reumatoidni artritis[37] i kancer.[38]

Kod ljudi, heterozigotne mutacije TBX3 dovode do autosomno dominantnog razvojnog poremećaja, sindroma ulnusne dojke (UMS), koji se odlikuje nizom kliničkih značajki,uključujući hipoplaziju mliječnih i apokrinih žlijezda, defekte gornjih udova, malformacije areola, zubne strukture, srca i genitalija.[8][39] Prijavljeno je nekoliko UMS-a koji uzrokuju mutacije u TBX3 genu, uključujući pet nonsens mutacija, osam pomaka okvira (zbog delecija, duplikacija i insercija), tri misens mutacije i dvije mutacije na mjestu prerade. Misens mutacije unutar T-domen ili gubitak RD1 rezultiraju aberantnim transkriptima i krnjim proteinima TBX3. Ove mutacije dovode do smanjenja vezivanja DNK, kontrole transkripcije i regulacije prerade TBX3 i gubitka funkcije, a povezane su s najtežim fenotipom UMS-a.[22][40][41][42]

Tbx3 je eksprimiran u heterogenim populacijama neurona jezgara hipotalamusnog luka, koja kontroliraju energetsku homeostazu, regulirajući apetit i potrošnju energije, a pokazalo se da ablacija funkcije TBX3 u tim neuronima uzrokuje pretilost na modelima miša. Važno je napomenuti da se pokazalo da je Tbx3 ključni faktor u pokretanju funkcionalne heterogenosti hipotalamusnih neurona, a ta je funkcija konzervirana kod miševa, drozofila i ljudi, za osjetljivost na reumatoidni artritis (RA), a nedavno je istraživanje identificiralo Tbx3 kao gen kandidat za RA u mišjim modelima izazvanim kolagenom artritisom (CIA).[37][43] Ozbiljnost RA direktno je povezana sa serumskim nivoima TBX3 u modelima CIA miša. Nadalje, pokazalo se da Tbx3 potiskuje proliferaciju B-limfocita i aktivira humoralni imunski odgovor, koji je povezan s hroničnom upalom sinovijalnih žlijezda, što dovodi do RA. Tbx3 bi stoga mogao biti važan faktor u regulaciji imunskog sistema i mogao bi se koristiti kao biomarker za dijagnozu ozbiljnosti RA.

TBX3 je prekomjerno izražen u širokom rasponu karcinoma (karcinom dojke, gušterače, melanom, rak jetre, pluća, želuca, jajnika, mjehura i glave i vrata) i sarkoma (hondrosarkom, fibrosarkom, liposarkom, rabdomiosarkom i sinovijalni sarkom) te doprinosi nekoliko obilježja raka. Zaista, TBX3 može zaobići ćelijsko starenje, apoptozu i anoikis, kao i podsticati nekontroliranu proliferaciju ćelija, stvaranje tumora, angiogenezu i metastaze.[44][45][46] Nadalje, TBX3 doprinosi širenju matičnih ćelija raka (CSC) i ključni je faktor u regulaciji gena povezanih pluripotencijom u tim ćelijama. CSC doprinosi recidivu tumora i gubitak otpornosti , pa ovo može biti još jedan mehanizam pomoću TBX3 doprinosi stvaranju raka i agresivnosti tumora.[47] Mehanizmi pomoću kojih TBX3 doprinosi onkogenim procesima djelimično uključuju njegovu sposobnost da inhibira puteve supresije tumora p14ARF/p53/p21WAF1/CIP1,[32][48] p16INK4a/pRb, p57KIP2,[49] PTEN,[25] E-cadherin[44][45] and activating the angiogenesis-associated genes FGF2 and VEGF-A[50] i EMT gena SNAI.

Reference

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