ESR1
Estrogeni receptor alfa (ERα), znan i kao NR3A1 (član 1grupe A potporodice jedarnih receptora), jedan je od dva tipa estrogenih receptora, jedarni receptor koji se aktivira spolnim hormonom estrogenom. Kod ljudi kodiran genom ESR1 (Estrogeni receptor 1).[5][6][7]
Aminokiselinska sekvenca
[uredi | uredi izvor]Dužina polipeptidnog lanca je 595 aminokiselina, а molekulska težina 66.216 Da.[8]
10 | 20 | 30 | 40 | 50 | ||||
---|---|---|---|---|---|---|---|---|
MTMTLHTKAS | GMALLHQIQG | NELEPLNRPQ | LKIPLERPLG | EVYLDSSKPA | ||||
VYNYPEGAAY | EFNAAAAANA | QVYGQTGLPY | GPGSEAAAFG | SNGLGGFPPL | ||||
NSVSPSPLML | LHPPPQLSPF | LQPHGQQVPY | YLENEPSGYT | VREAGPPAFY | ||||
RPNSDNRRQG | GRERLASTND | KGSMAMESAK | ETRYCAVCND | YASGYHYGVW | ||||
SCEGCKAFFK | RSIQGHNDYM | CPATNQCTID | KNRRKSCQAC | RLRKCYEVGM | ||||
MKGGIRKDRR | GGRMLKHKRQ | RDDGEGRGEV | GSAGDMRAAN | LWPSPLMIKR | ||||
SKKNSLALSL | TADQMVSALL | DAEPPILYSE | YDPTRPFSEA | SMMGLLTNLA | ||||
DRELVHMINW | AKRVPGFVDL | TLHDQVHLLE | CAWLEILMIG | LVWRSMEHPG | ||||
KLLFAPNLLL | DRNQGKCVEG | MVEIFDMLLA | TSSRFRMMNL | QGEEFVCLKS | ||||
IILLNSGVYT | FLSSTLKSLE | EKDHIHRVLD | KITDTLIHLM | AKAGLTLQQQ | ||||
HQRLAQLLLI | LSHIRHMSNK | GMEHLYSMKC | KNVVPLYDLL | LEMLDAHRLH | ||||
APTSRGGASV | EETDQSHLAT | AGSTSSHSLQ | KYYITGEAEG | FPATV |
Struktura
[uredi | uredi izvor]Receptor estrogena (ER) je ligand-aktivirani transkripcijski faktor sastavljen od nekoliko domena važnih za vezivanje hormona, vezanjem i aktivacijom transkripcije.[9] Alternativna prerada rezultira u nekoliko transkripata ESR1 iRNK, koji se prvenstveno razlikuju po pet primarnih neprevedenih regija (UTR5'). Translatirani receptori pokazuju manju varijabilnost.[10][11]
Agonisti
[uredi | uredi izvor]Neselektivni
[uredi | uredi izvor]- Endogeni estrogeni (npr. estradiol, estron, estriol, estetrol)
- prirodni estrogeni (npr. konjugirani konjski estrogeni)
- Sintetski estrogeni (npr. etinilestradiol, dietilstilbestrol)
Selektivni
[uredi | uredi izvor]Selektivni agonisti ERα u odnosu na ERβ uključuju:
- Propilpirazoletriol (PPT)
- 16α-LE2 (Cpd1471)
- 16α-IE2
- ERA-63 (ORG-37663)
- SKF-82.958 – također receptor sličan D1]potpuni agonist
- (R, R) -Tetrahidrohrisen, (R, R)-THC) – zapravo nije selektivan u odnosu na ERβ, već je antagonist umjesto agonista ERβ
Mješoviti
[uredi | uredi izvor]- Fitoestrogeni (npr. kumestrol, daidzein, genistein, miroestrol)
- Selektivni modulatori estrogenog eceptora (npr. tamoksifen, klomifen, raloksifen)
Antagonisti
[uredi | uredi izvor]Neselektivni
[uredi | uredi izvor]Selektivni
[uredi | uredi izvor]Selektivni antagonisti ERα u odnosu na ERβ uključuju:
- Metilpiperidinopirazol (MPP)
Afiniteti
[uredi | uredi izvor]Šablon:Afiniteti liganda estrogenog receptora ERα i ERβ
Tkivna distribucija i funkcija
[uredi | uredi izvor]ERα ima ulogu u fiziološkom razvoju i funkciji različitih organskih sistema u različitom stepenu, uključujući reproduktivni, centralni nervni, skeletni i kardiovaskularni sistem.[12] U skladu s tim, ERα je široko eksprimiran u cijelom tijelu, uključujući tkiva organa kao što su maternica i jajnici, muški reproduktivni organi, mliječne žlijezde, kosti, srce, hipotalamus, hipofiza, jetra, pluća, bubrezi, slezena i masno tkivo .[12][13][14] Razvoj i funkcija ovih tkiva poremećen je u životinjskim modelima bez aktivnih ERα gena, poput ERα nokaut-miša (ERKO), pružajući prethodno razumijevanje funkcije ERα u specifičnim ciljanim organima.[12][15]
Klinički značaj
[uredi | uredi izvor]Sindrom neosjetljivosti na estrogene je vrlo rijetko stanje koje karakterizira neispravan Erα, neosjetljiv na estrogene.[16][17][18][19] Uočeno je da klinička slika žena uključuje odsustvo razvoja dojke i drugih ženskih sekundarsnih spolnih obilježja u pubertetu, hipoplaziji maternice, primarnoj amenoreji, pri uvećanim policistastim jajnicima i pridruženom bolu u donjem dijelu trbuha, blagi hiperandrogenizam (ispoljava se kao cistaste akne) i odgođeno sazrijevanje kosti kao i povećana stopa koštanog promedta. Klinička slika kod mužjaka je uključivala nedostatak zatvaranja epifize, visok rast, osteoporozu i lošu održivost spermatozoida. Obje posmstrane osobe bile su potpuno neosetljive na egzogeni tretman estrogenom, čak i pri visokim dozama.
Genetički polimorfizmi u genu koji kodira ERα povezani su sa rakom dojke i dismenorejom kod žena, a ginekomastijom kod muškaraca.[20][21][22]
Koaktivatori
[uredi | uredi izvor]Koaktivatori ER-α uključuju:
- SRC-1[23][24]
- AIB1 – amplified in breast 1[25]
- BCAS3 – amplificirana sekvenca karcinoma dojke 3[26]
- PELP-1 – Prolinom-, glutamatom-, leucinom-bogati protein 1[27]
Interakcije
[uredi | uredi izvor]Pokazano je da receptor estrogena alfa stupa u interakcije sa:
- AKAP13[28]
- AHR[29][30]
- BRCA1[31][32][33][34]
- CAV1[35]
- CCNC[36]
- CDC25B[37]
- CEBPB[38][39]
- COBRA1[40]
- COUP-TFI[41]
- CREBBP[34][42]
- CRSP3[36]
- Ciklin D1[43]
- DDX17[44]
- DDX5[44][45]
- DNTTIP2[46]
- EP300[34][36][47]
- ESR2[48][49]
- FOXO1[50]
- GREB1[51]
- GTF2H1[52]
- HSP90AA1[53][54]
- ISL1[55]
- JARID1A[56]
- MVP[57]
- MED1[36][58]
- MED12[36]
- MED14[36]
- MED16[36]
- MED24[36][58]
- MED6[36]
- MGMT[59]
- MNAT1[60]
- MTA1[61][62]
- NCOA6[63][64]
- NCOA1[36][42][44][65][66]
- NCOA2[44][58][67][68][69]
- NCOA3[44][70][71]
- NRIP1[72][73][74]
- PDLIM1[75]
- POU4F1[76]
- POU4F2[76]
- PRDM2[77]
- PRMT2[78]
- RBM39[79]
- RNF12[75]
- SAFB[80][81]
- SAFB2[82]
- SHC1[83]
- SHP[84][85]
- SMARCA4[65][86]
- SMARCE1[87]
- SRA1[44]
- Src[59][88][89][90]
- TR2[91]
- TR4[92]
- TDG[93]
- TRIM24[73][94] i
- XBP1.[95]
Reference
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Vanjski linkovi
[uredi | uredi izvor]Ovaj članak uključuje tekst iz Nacionalne medicinske biblioteke Sjedinjenih Država, koji je u javnom vlasništvu.