NDRG1
Protein NDRG1 je protein koji je kod ljudi kodiran genom NDRG1.[5][6][7][8]
Ovaj gen je član N-myc porodice podreguliranih gena, koja pripada natporodici alfa/beta hidrolaza. Protein kodiran ovim genom je citoplazmatski protein koji učestvuje u odgovorima na stres, odgovorima hormona, rastu i diferencijaciji ćelija. Zabilježeno je da su mutacije u ovom genu uzročnici autosomno-recesivne verzije Charcot-Marie-Toothove bolesti, poznate kao CMT4D.[8]
Zabilježeno je da se NDRG1 lokalizira u endosomima i da je Rab4a efektor uključen u reciklažu vezikula.[9]
Prema pregledu koji su uradili Fang et al.,[10] NDRG1 je uključen u embriogenezu i razvoj, rast i diferencijaciju ćelija, biosintezu i mijelinizaciju lipida, reakcije na stres, imunost, popravak DNK i adheziju ćelija između ostalih funkcija. NDRG1 je lokaliziran u citoplazmi, jedru i mitohondrijama, s vjerovatnostima od 47,8%, odnosno 26,1% i 8,7%. Kao odgovor na oštećenje DNK, NDRG1 se prebacuje iz citoplazme u jedro, gdje može inhibirati rast ćelija i podstaknuti mehanizme popravljanja DNK. Predlaže se da NDRG1 djeluje kao gen za odgovor na stres ili potencijalno kao transkripcijski faktor.
Aminokiselinska sekvenca
urediDužina polipeptidnog lanca je 394 aminokiseline, а molekulska težina Da. 42 835[11]
| 10 | 20 | 30 | 40 | 50 | ||||
|---|---|---|---|---|---|---|---|---|
| MSREMQDVDL | AEVKPLVEKG | ETITGLLQEF | DVQEQDIETL | HGSVHVTLCG | ||||
| TPKGNRPVIL | TYHDIGMNHK | TCYNPLFNYE | DMQEITQHFA | VCHVDAPGQQ | ||||
| DGAASFPAGY | MYPSMDQLAE | MLPGVLQQFG | LKSIIGMGTG | AGAYILTRFA | ||||
| LNNPEMVEGL | VLINVNPCAE | GWMDWAASKI | SGWTQALPDM | VVSHLFGKEE | ||||
| MQSNVEVVHT | YRQHIVNDMN | PGNLHLFINA | YNSRRDLEIE | RPMPGTHTVT | ||||
| LQCPALLVVG | DSSPAVDAVV | ECNSKLDPTK | TTLLKMADCG | GLPQISQPAK | ||||
| LAEAFKYFVQ | GMGYMPSASM | TRLMRSRTAS | GSSVTSLDGT | RSRSHTSEGT | ||||
| RSRSHTSEGT | RSRSHTSEGA | HLDITPNSGA | AGNSAGPKSM | EVSC |
Gen
urediKod ljudi, gen NDRG1 nalazi se na dugom kraku hromosoma 8, sekvenca (8q24.22). Gen kodira 3,0 kilobazne (kb) informacijske RNK (iRNK) sastavljene od 394 aminokiseline. NDRG1 pripadaju porodici NDRG1, koja se sastoji od četiri člana – NDRG1, NDRG2, NDRG3 i NDRG4 – koji dijele 53-65 % homologije. Za razliku od drugih članova porodice, NDRG1 ima tri tandemska (GTRSRSHTSE) ponavljanja u C-terminalnom dijelu.[12][13]
Ekspresija NDRG1 regulirana je hipoksijom-ovisnim i neovisnim načinom. Pod hipoksijom se senzor kisika faktora induciranog hipoksijom (HIF) -1α translocira iz citoplazme u jedro, gdje se veže za HIF-1β, kako bi formirao kompleks HIF-1. Ovaj kompleks djeluje kao transkripcijski faktor, veže se na element odgovora na hipoksiju (HRE) u promotoru gena povezanih s hipoksijom; jedan od tih gena je NDRG1.[14] Ioni teških metala (nikl, kobalt, gvožđe) pojačavaju NDRG1, oponašajući hipoksiju. Suprotan učinak na ekspresiju NDRG1 mogli bi imati myc onkoproteini, N-myc i c-myc, koji transkripcijski potiskuju ekspresiju. Ovi učinci posredno se posreduju smanjenjem njegove promotorske aktivnosti.[10]
Uloga u kanceru
urediPrema pregledu Kovačevića et al.,[15] NDRG1 je snažan supresor rasta i metastaza, reguliran gvožđem, za koji je utvrđeno da je u negativnoj korelaciji s progresijom raka u brojnim tumorima, uključujući karcinom prostate, gušterače, dojke i debelog crijeva. NDRG1 ima izrazito antionkogeno djelovanje, povezano sa smanjenom proliferacijom ćelija, migracijom, invazijom i angiogenezom. Molekulske funkcije NDRG1 utiču na brojne signalne puteve koji reguliraju proliferaciju ćelija raka, invaziju, angiogenezu i migraciju. Konkretno, NDRG1 inhibira onkogeni RAS, c-Src, fosfatidilinozitol 3-kinazu (PI3K), WNT, ROCK1/pMLC2 i jedarni faktor-pojačivač lahkog lanca puteva aktiviranih B-ćelija (NF-B), dok podstiče ekspresiju ključnog tumora – supresivne molekule uključujući fosfatazu i homolog tenzina, E-kadherin i majke protiv dekapentaplegijskog homologa 4 (SMAD4). Svojim djelovanjem na E-kadherin i beta-katenin, koji tvore adherensko spajanje i podstiču adheziju ćelija, NDRG1 također inhibira epitelno-mezenhimu tranziciju, početni ključni korak u metastaziranju.
Funkcije u popravljanju i starenju DNK
urediU jednoj od svojih funkcija na molekulnom nivou, NDRG1 veže i stabilizira metiltransferaze, uglavnom O-6-metilguanin-DNK metiltransferaza+u (MGMT),[16] protein popravke DNK. Dakle, veća ekspresija NDRG1 može podstaknuti stabilnost i aktivnost proteina MGMT. Dominick et al.[17] pokazali su da je ekspresija proteina NDRG1 i MGMT povećana 2–3 puta za svaki od tri soja miševa (Snell, GHKRO i PAPPA-KO) s povećanom dugovječnošću. Ovi autori snažno ukazuju na vezu između povećanja puta popravljanja DNK MGMT i kašnjenja u procesu starenja ovih sojeva miša. To je u skladu s teorijom starenja oštrćenjem DNK.
Uloga u imunskom sistemu
urediNDRG1 ima važnu ulogu u alergijama i anafilaksiji, odbrani od bakterijskih patogena i bakterijskog uklanjanja, upala i zacjeljivanja rana. U mastocitima, NDRG1 je tokom zrenja povećano reguliran i pomaže brzoj degranulaciji, što dovodi do pojačane egzocitoze, kao odgovor na različite podražaje.[18] Također je pokazana njegova uloga u klonskoj anergiji T-ćelija nizvodno od Egr2, gdje je NDRG1 pojačano reguliran u nedostatku kostimulacije, kako bi se spriječila naknadna reaktivacija T-ćelija, TCR i CD28 signalizacijom.[19]
Reference
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