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NRAS
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Pogledaj/uredi – čovjek

NRAS jest enzim koji je kod ljudi kodiran genom NRAS sa hromosoma 1. Otkrio ga je mali tim istraživača na čelu sa Robinom Weissom na Institute of Cancer Research u Londonu.^[1]^[2] Bio je to trećeotkriveni gen RAS, a nazvan je NRAS, za njegovu početnu identifikaciju u ljudskim neuroblastomskim ćelijama.

Aminokiselinska sekvenca

Dužina polipeptidnog lanca je 189 aminokiselina, a molekulska težina Da. 21.229^[3]

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

10	20	30	40	50
MTEYKLVVVG	AGGVGKSALT	IQLIQNHFVD	EYDPTIEDSY	RKQVVIDGET
CLLDILDTAG	QEEYSAMRDQ	YMRTGEGFLC	VFAINNSKSF	ADINLYREQI
KRVKDSDDVP	MVLVGNKCDL	PTRTVDTKQA	HELAKSYGIP	FIETSAKTRQ
GVEDAFYTLV	REIRQYRMKK	LNSSDDGTQG	CMGLPCVVM

Funkcija

N-ras proto-onkogen je član Ras porodice gena. Mapira se na hromosomu 1 i aktivira u HL60, liniji promijelocitne leukemije. Redoslijed obližnjih gena je sljedeći: cen—CD2—NGFB—NRAS—tel.

Porodica sisarskih ras gena sastoji se od harvey i kirsten ras gena (HRAS i KRAS), neaktivnog pseudogena svakog (c-Hras2 i c-Kras1) i N-ras gena. Značajno se razlikuju samo u 40 C-terminalnih aminokiselina. Ovi ras geni imaju GTP/GDP vezu i aktivnost GTPaze, a njihova normalna funkcija može biti kao G-slični regulatorni proteini uključeni u normalnu kontrolu rasta ćelija.

N-ras gen specificira dva glavna transkripta od 2Kb i 4.3Kb. Razlika između ova dva transkripta je jednostavno proširenje kroz mjesto završetka 2Kb transkripta. N-ras gen se sastoji od sedam egzona (I, I, II, III, IV, V, VI). Manji transkript od 2Kb sadrži VIa egzon, a veći, od 4,3Kb, sadrži VIb egzon koji je samo duži oblik VIa egzona. Oba transkripta kodiraju identične proteine jer se razlikuju samo u 3' neprevedenoi regiji.^[4]

Mutacije

Mutacije koje mijenjaju aminokiselinske ostatke 12, 13 ili 61 aktiviraju potencijal N-ras za transformaciju kultiviranih ćelija i uključene su u različite ljudske tumore^[4] npr. melanom.

Kao cilj lijekova

Binimetinib (MEK162) je imao kliničko ispitivanje faze III za NRAS Q61 mutant melanoma.^[5]

Reference

^ Marshall CJ, Hall A, Weiss RA (septembar 1982). "A transforming gene present in human sarcoma cell lines". Nature. 299 (5879): 171–3. Bibcode:1982Natur.299..171M. doi:10.1038/299171a0. PMID 6287287. S2CID 4342747.
^ Shimizu K, Goldfarb M, Perucho M, Wigler M (januar 1983). "Isolation and preliminary characterization of the transforming gene of a human neuroblastoma cell line". PNAS. 80 (2): 383–7. Bibcode:1983PNAS...80..383S. doi:10.1073/pnas.80.2.383. PMC 393381. PMID 6300838.
^ "UniProt, P01111" (jezik: eng.). Pristupljeno 3. 12. 2021.CS1 održavanje: nepoznati jezik (link)
^ ^a ^b "Entrez Gene: NRAS neuroblastoma RAS viral (v-ras) oncogene homolog".
^ Study Comparing the Efficacy of MEK162 Versus Dacarbazine in Unresectable or Metastatic NRAS Mutation-positive Melanoma

Dopunska ligteratura

McCormick F (1996). "Ras-related proteins in signal transduction and growth control". Mol. Reprod. Dev. 42 (4): 500–6. doi:10.1002/mrd.1080420419. PMID 8607982. S2CID 6507743.
van Elsas A, Scheibenbogen C, van der Minne C, et al. (1998). "UV-induced N-ras mutations are T-cell targets in human melanoma". Melanoma Res. 7 Suppl 2: S107–13. doi:10.1097/00008390-199708001-00017. PMID 9578425. S2CID 19219505.
Dracopoli NC, Meisler MH (1990). "Mapping the human amylase gene cluster on the proximal short arm of chromosome 1 using a highly informative (CA)n repeat" (PDF). Genomics. 7 (1): 97–102. doi:10.1016/0888-7543(90)90523-W. hdl:2027.42/28584. PMID 1692298.
Yuasa Y, Kamiyama T, Kato M, et al. (1990). "Transforming genes from familial adenomatous polyposis patient cells detected by a tumorigenicity assay". Oncogene. 5 (4): 589–96. PMID 1970154.
Hancock JF, Magee AI, Childs JE, Marshall CJ (1989). "All ras proteins are polyisoprenylated but only some are palmitoylated". Cell. 57 (7): 1167–77. doi:10.1016/0092-8674(89)90054-8. PMID 2661017.
Hall A, Brown R (1985). "Human N-ras: cDNA cloning and gene structure". Nucleic Acids Res. 13 (14): 5255–68. doi:10.1093/nar/13.14.5255. PMC 321863. PMID 2991860.
Hirai H, Tanaka S, Azuma M, et al. (1986). "Transforming genes in human leukemia cells". Blood. 66 (6): 1371–8. doi:10.1182/blood.V66.6.1371.1371. PMID 2998510.
Neri A, Knowles DM, Greco A, et al. (1988). "Analysis of RAS oncogene mutations in human lymphoid malignancies". Proc. Natl. Acad. Sci. U.S.A. 85 (23): 9268–72. Bibcode:1988PNAS...85.9268N. doi:10.1073/pnas.85.23.9268. PMC 282720. PMID 3057505.
Nitta N, Ochiai M, Nagao M, Sugimura T (1987). "Amino-acid substitution at codon 13 of the N-ras oncogene in rectal cancer in a Japanese patient". Jpn. J. Cancer Res. 78 (1): 21–6. PMID 3102434.
Raybaud F, Noguchi T, Marics I, et al. (1988). "Detection of a low frequency of activated ras genes in human melanomas using a tumorigenicity assay". Cancer Res. 48 (4): 950–3. PMID 3276402.
Hirai H, Kobayashi Y, Mano H, et al. (1987). "A point mutation at codon 13 of the N-ras oncogene in myelodysplastic syndrome". Nature. 327 (6121): 430–2. Bibcode:1987Natur.327..430H. doi:10.1038/327430a0. PMID 3295562.
Gambke C, Hall A, Moroni C (1985). "Activation of an N-ras gene in acute myeloblastic leukemia through somatic mutation in the first exon". Proc. Natl. Acad. Sci. U.S.A. 82 (3): 879–82. Bibcode:1985PNAS...82..879G. doi:10.1073/pnas.82.3.879. PMC 397150. PMID 3856237.
Padua RA, Barrass NC, Currie GA (1985). "Activation of N-ras in a human melanoma cell line". Mol. Cell. Biol. 5 (3): 582–5. doi:10.1128/mcb.5.3.582. PMC 366752. PMID 3887133.
Brown R, Marshall CJ, Pennie SG, Hall A (1984). "Mechanism of activation of an N-ras gene in the human fibrosarcoma cell line HT1080". EMBO J. 3 (6): 1321–6. doi:10.1002/j.1460-2075.1984.tb01970.x. PMC 557516. PMID 6086315.
Yuasa Y, Gol RA, Chang A, et al. (1984). "Mechanism of activation of an N-ras oncogene of SW-1271 human lung carcinoma cells". Proc. Natl. Acad. Sci. U.S.A. 81 (12): 3670–4. Bibcode:1984PNAS...81.3670Y. doi:10.1073/pnas.81.12.3670. PMC 345280. PMID 6587382.
Taparowsky E, Shimizu K, Goldfarb M, Wigler M (1983). "Structure and activation of the human N-ras gene". Cell. 34 (2): 581–6. doi:10.1016/0092-8674(83)90390-2. PMID 6616621. S2CID 39787991.
Mitchell EL, Jones D, White GR, et al. (1995). "Determination of the gene order of the three loci CD2, NGFB, and NRAS at human chromosome band 1p13 and refinement of their localisation at the subband level by fluorescence in situ hybridisation". Cytogenet. Cell Genet. 70 (3–4): 183–5. doi:10.1159/000134028. PMID 7789166.
Kodaki T, Woscholski R, Hallberg B, et al. (1995). "The activation of phosphatidylinositol 3-kinase by Ras". Curr. Biol. 4 (9): 798–806. doi:10.1016/S0960-9822(00)00177-9. PMID 7820549. S2CID 20836474.
Rodriguez-Viciana P, Warne PH, Vanhaesebroeck B, et al. (1996). "Activation of phosphoinositide 3-kinase by interaction with Ras and by point mutation". EMBO J. 15 (10): 2442–51. doi:10.1002/j.1460-2075.1996.tb00602.x. PMC 450176. PMID 8665852.

Vanjski linkovi

GeneReviews/NCBI/NIH/UW entry on Noonan syndrome

[pmid6287287-1] Marshall CJ, Hall A, Weiss RA (septembar 1982). "A transforming gene present in human sarcoma cell lines". Nature. 299 (5879): 171–3. Bibcode:1982Natur.299..171M. doi:10.1038/299171a0. PMID 6287287. S2CID 4342747.

[pmid6300838-2] Shimizu K, Goldfarb M, Perucho M, Wigler M (januar 1983). "Isolation and preliminary characterization of the transforming gene of a human neuroblastoma cell line". PNAS. 80 (2): 383–7. Bibcode:1983PNAS...80..383S. doi:10.1073/pnas.80.2.383. PMC 393381. PMID 6300838.

[UniProt-3] "UniProt, P01111" (jezik: eng.). Pristupljeno 3. 12. 2021.CS1 održavanje: nepoznati jezik (link)

[entrez-4] "Entrez Gene: NRAS neuroblastoma RAS viral (v-ras) oncogene homolog".

[NCT01763164-5] Study Comparing the Efficacy of MEK162 Versus Dacarbazine in Unresectable or Metastatic NRAS Mutation-positive Melanoma

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NRAS