NDRG1

NDRG1
Identifikatori
Aliasi	NDRG1
Vanjski ID-jevi	OMIM: 605262 MGI: 1341799 HomoloGene: 55953 GeneCards: NDRG1
Lokacija gena (čovjek) Hrom. Hromosom 8 (čovjek)[1] Bend 8q24.22 Početak 133,237,175 bp[1] Kraj 133,302,022 bp[1]
Lokacija gena (miš) Hrom. Hromosom 15 (miš)[2] Bend 15|15 D2 Početak 66,801,167 bp[2] Kraj 66,841,489 bp[2]
Obrazac RNK ekspresije Više referentnih podataka o ekspresiji
Ontologija gena Molekularna funkcija • microtubule binding • cadherin binding • GO:0001948, GO:0016582 vezivanje za proteine • gamma-tubulin binding Ćelijska komponenta • citoplazma • centrosom • membrana • microtubule cytoskeleton • myelin sheath • ćelijska membrana • centar organizacije mikrotubula • recycling endosome membrane • perinuklearno područje citoplazme • Mikrotubula • Egzosom • citoskelet • jedro • citosol • glutamatergic synapse Biološki proces • mast cell activation • peripheral nervous system myelin maintenance • DNA damage response, signal transduction by p53 class mediator • response to metal ion • positive regulation of spindle checkpoint • regulation of cell population proliferation • cellular response to hypoxia • negative regulation of cell population proliferation • regulation of apoptotic process • GO:0072468 Transdukcija signala • postsynapse organization Izvori:Amigo / QuickGO
Ortolozi
Vrste	Čovjek	Miš
Entrez	10397	17988
Ensembl	ENSG00000104419	ENSMUSG00000005125
UniProt	Q92597	Q62433
RefSeq (mRNK)	NM_001135242 NM_001258432 NM_001258433 NM_006096 NM_001374844 NM_001374845 NM_001374846 NM_001374847	NM_008681
RefSeq (bjelančevina)	NP_001128714 NP_001245361 NP_001245362 NP_006087 NP_001361773 NP_001361774 NP_001361775 NP_001361776	NP_032707
Lokacija (UCSC)	Chr 8: 133.24 – 133.3 Mb	Chr 15: 66.8 – 66.84 Mb
PubMed pretraga	[3]	[4]
Wikipodaci
Pogledaj/uredi – čovjek Pogledaj/uredi – miš

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

Dužina 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

C: Cistein
D: Aspartat
E: Glutamat
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

Gen

Kod 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

Prema 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

U 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

NDRG1 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

1. GRCh38: Ensembl release 89: ENSG00000104419 - Ensembl, maj 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000005125 - Ensembl, maj 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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7. Zhang J, Chen S, Zhang W, Zhang J, Liu X, Shi H, et al. (juli 2008). "Human differentiation-related gene NDRG1 is a Myc downstream-regulated gene that is repressed by Myc on the core promoter region". Gene. 417 (1–2): 5–12. doi:10.1016/j.gene.2008.03.002. PMID 18455888.
8. "Entrez Gene: NDRG1 N-myc downstream regulated gene 1".
9. Kachhap SK, Faith D, Qian DZ, Shabbeer S, Galloway NL, Pili R, et al. (septembar 2007). Heisenberg C (ured.). "The N-Myc down regulated Gene1 (NDRG1) Is a Rab4a effector involved in vesicular recycling of E-cadherin". PLOS ONE. 2 (9): e844. Bibcode:2007PLoSO...2..844K. doi:10.1371/journal.pone.0000844. PMC 1952073. PMID 17786215.
10. Fang BA, Kovačević Ž, Park KC, Kalinowski DS, Jansson PJ, Lane DJ, et al. (januar 2014). "Molecular functions of the iron-regulated metastasis suppressor, NDRG1, and its potential as a molecular target for cancer therapy". Biochimica et Biophysica Acta (BBA) - Reviews on Cancer. 1845 (1): 1–19. doi:10.1016/j.bbcan.2013.11.002. PMID 24269900.
11. "UniProt, Q92597" (jezik: engleski). Pristupljeno 20. 9. 2021.
12. Sahni S, Park KC, Kovacevic Z, Richardson DR (juni 2019). "Two mechanisms involving the autophagic and proteasomal pathways process the metastasis suppressor protein, N-myc downstream regulated gene 1". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1865 (6): 1361–1378. doi:10.1016/j.bbadis.2019.02.008. PMID 30763642.
13. Sun J, Zhang D, Bae DH, Sahni S, Jansson P, Zheng Y, et al. (septembar 2013). "Metastasis suppressor, NDRG1, mediates its activity through signaling pathways and molecular motors". Carcinogenesis. 34 (9): 1943–54. doi:10.1093/carcin/bgt163. PMID 23671130.
14. Park KC, Paluncic J, Kovacevic Z, Richardson DR (maj 2019). "Pharmacological targeting and the diverse functions of the metastasis suppressor, NDRG1, in cancer". Free Radical Biology & Medicine. 157: 154–175. doi:10.1016/j.freeradbiomed.2019.05.020. PMID 31132412.
15. Kovacevic Z, Menezes SV, Sahni S, Kalinowski DS, Bae DH, Lane DJ, Richardson DR (januar 2016). "The Metastasis Suppressor, N-MYC Downstream-regulated Gene-1 (NDRG1), Down-regulates the ErbB Family of Receptors to Inhibit Downstream Oncogenic Signaling Pathways". The Journal of Biological Chemistry. 291 (3): 1029–52. doi:10.1074/jbc.M115.689653. PMC 4714189. PMID 26534963.
16. Weiler M, Blaes J, Pusch S, Sahm F, Czabanka M, Luger S, et al. (januar 2014). "mTOR target NDRG1 confers MGMT-dependent resistance to alkylating chemotherapy". Proceedings of the National Academy of Sciences of the United States of America. 111 (1): 409–14. Bibcode:2014PNAS..111..409W. doi:10.1073/pnas.1314469111. PMC 3890826. PMID 24367102.
17. Dominick G, Bowman J, Li X, Miller RA, Garcia GG (februar 2017). "mTOR regulates the expression of DNA damage response enzymes in long-lived Snell dwarf, GHRKO, and PAPPA-KO mice". Aging Cell. 16 (1): 52–60. doi:10.1111/acel.12525. PMC 5242303. PMID 27618784.
18. Kovacevic Z, Richardson DR (decembar 2006). "The metastasis suppressor, Ndrg-1: a new ally in the fight against cancer". Carcinogenesis. 27 (12): 2355–66. doi:10.1093/carcin/bgl146. PMID 16920733.
19. Oh YM, Park HB, Shin JH, Lee JE, Park HY, Kho DH, et al. (oktobar 2015). "Ndrg1 is a T-cell clonal anergy factor negatively regulated by CD28 costimulation and interleukin-2". Nature Communications. 6 (1): 8698. Bibcode:2015NatCo...6.8698O. doi:10.1038/ncomms9698. PMC 4846325. PMID 26507712.

Dopunska literatura

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Vanjski linkovi

• GeneReviews/NCBI/NIH/UW entry on Charcot-Marie-Tooth Neuropathy Type 4