TBX3

S Wikipedije, slobodne enciklopedije
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

6926

21386

Ensembl

ENSG00000135111

ENSMUSG00000018604

UniProt

O15119

P70324

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[uredi | uredi izvor]

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[uredi | uredi izvor]

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

C: Cistein
D: Asparaginska kiselina
E: Glutaminska kiselina
F: Fenilalanin
G: Glicin
H: Histidin
I: Izoleucin
K: Lizin
L: Leucin
M: Metionin
N: Asparagin
P: Prolin
Q: Glutamin
R: Arginin
S: Serin
T: Treonin
V: Valin
W: Triptofan
Y: Tirozin

Struktura i funkcija[uredi | uredi izvor]

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[uredi | uredi izvor]

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[uredi | uredi izvor]

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