Neuroblastoma RAS viral oncogene homolog
NRAS is an enzyme that in humans is encoded by the NRAS gene. It was discovered by a small team of researchers led by Robin Weiss at the Institute of Cancer Research in London.[5][6] It was the third RAS gene to be discovered, and was named NRAS, for its initial identification in human neuroblastoma cells.
Function
The N-ras proto-oncogene is a member of the Ras gene family. It is mapped on chromosome 1, and it is activated in HL60, a promyelocytic leukemia line. The order of nearby genes is as follows: cen—CD2—NGFB—NRAS—tel.
The mammalian ras gene family consists of the harvey and kirsten ras genes (HRAS and KRAS), an inactive pseudogene of each (c-Hras2 and c-Kras1) and the N-ras gene. They differ significantly only in the C-terminal 40 amino acids. These ras genes have GTP/GDP binding and GTPase activity, and their normal function may be as G-like regulatory proteins involved in the normal control of cell growth.
The N-ras gene specifies two main transcripts of 2Kb and 4.3Kb. The difference between the two transcripts is a simple extension through the termination site of the 2Kb transcript. The N-ras gene consists of seven exons (-I, I, II, III, IV, V, VI). The smaller 2Kb transcript contains the VIa exon, and the larger 4.3Kb transcript contains the VIb exon which is just a longer form of the VIa exon. Both transcripts encode identical proteins as they differ only the 3' untranslated region.[7]
Mutations
Mutations which change amino acid residues 12, 13 or 61 activate the potential of N-ras to transform cultured cells and are implicated in a variety of human tumors[7] e.g. melanoma.
As a drug target
Binimetinib (MEK162) has had a phase III clinical trial for NRAS Q61 mutant melanoma.[8]
References
- 1 2 3 GRCh38: Ensembl release 89: ENSG00000213281 - Ensembl, May 2017
- 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000027852 - Ensembl, May 2017
- ↑ "Human PubMed Reference:".
- ↑ "Mouse PubMed Reference:".
- ↑ Marshall CJ, Hall A, Weiss RA (September 1982). "A transforming gene present in human sarcoma cell lines". Nature. 299 (5879): 171–3. doi:10.1038/299171a0. PMID 6287287.
- ↑ Shimizu K, Goldfarb M, Perucho M, Wigler M (January 1983). "Isolation and preliminary characterization of the transforming gene of a human neuroblastoma cell line". PNAS. 80 (2): 383–7. doi:10.1073/pnas.80.2.383. PMC 393381. PMID 6300838.
- 1 2 "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
Further reading
- 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.
- 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.
- 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". Genomics. 7 (1): 97–102. doi:10.1016/0888-7543(90)90523-W. 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. 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. 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. 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. 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. 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. 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. 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.
- 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.
- 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. PMC 450176. PMID 8665852.
External links
PDB gallery | |
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 121p: STRUKTUR UND GUANOSINTRIPHOSPHAT-HYDROLYSEMECHANISMUS DES C-TERMINAL VERKUERZTEN MENSCHLICHEN KREBSPROTEINS P21-H-RAS  1aa9: HUMAN C-HA-RAS(1-171)(DOT)GDP, NMR, MINIMIZED AVERAGE STRUCTURE  1agp: THREE-DIMENSIONAL STRUCTURES AND PROPERTIES OF A TRANSFORMING AND A NONTRANSFORMING GLY-12 MUTANT OF P21-H-RAS  1bkd: COMPLEX OF HUMAN H-RAS WITH HUMAN SOS-1  1clu: H-RAS COMPLEXED WITH DIAMINOBENZOPHENONE-BETA,GAMMA-IMIDO-GTP  1crp: THE SOLUTION STRUCTURE AND DYNAMICS OF RAS P21. GDP DETERMINED BY HETERONUCLEAR THREE AND FOUR DIMENSIONAL NMR SPECTROSCOPY  1crq: THE SOLUTION STRUCTURE AND DYNAMICS OF RAS P21. GDP DETERMINED BY HETERONUCLEAR THREE AND FOUR DIMENSIONAL NMR SPECTROSCOPY  1crr: THE SOLUTION STRUCTURE AND DYNAMICS OF RAS P21. GDP DETERMINED BY HETERONUCLEAR THREE AND FOUR DIMENSIONAL NMR SPECTROSCOPY  1ctq: STRUCTURE OF P21RAS IN COMPLEX WITH GPPNHP AT 100 K  1gnp: X-RAY CRYSTAL STRUCTURE ANALYSIS OF THE CATALYTIC DOMAIN OF THE ONCOGENE PRODUCT P21H-RAS COMPLEXED WITH CAGED GTP AND MANT DGPPNHP  1gnq: X-RAY CRYSTAL STRUCTURE ANALYSIS OF THE CATALYTIC DOMAIN OF THE ONCOGENE PRODUCT P21H-RAS COMPLEXED WITH CAGED GTP AND MANT DGPPNHP  1gnr: X-RAY CRYSTAL STRUCTURE ANALYSIS OF THE CATALYTIC DOMAIN OF THE ONCOGENE PRODUCT P21H-RAS COMPLEXED WITH CAGED GTP AND MANT DGPPNHP  1he8: RAS G12V - PI 3-KINASE GAMMA COMPLEX  1iaq: C-H-RAS P21 PROTEIN MUTANT WITH THR 35 REPLACED BY SER (T35S) COMPLEXED WITH GUANOSINE-5'-[B,G-IMIDO] TRIPHOSPHATE  1ioz: Crystal Structure of the C-HA-RAS Protein Prepared by the Cell-Free Synthesis  1jah: H-RAS P21 PROTEIN MUTANT G12P, COMPLEXED WITH GUANOSINE-5'-[BETA,GAMMA-METHYLENE] TRIPHOSPHATE AND MAGNESIUM  1jai: H-RAS P21 PROTEIN MUTANT G12P, COMPLEXED WITH GUANOSINE-5'-[BETA,GAMMA-METHYLENE] TRIPHOSPHATE AND MANGANESE  1k8r: Crystal structure of Ras-Bry2RBD complex  1lf0: Crystal Structure of RasA59G in the GTP-bound form  1lf5: Crystal Structure of RasA59G in the GDP-bound Form  1lfd: CRYSTAL STRUCTURE OF THE ACTIVE RAS PROTEIN COMPLEXED WITH THE RAS-INTERACTING DOMAIN OF RALGDS  1nvu: Structural evidence for feedback activation by RasGTP of the Ras-specific nucleotide exchange factor SOS  1nvv: Structural evidence for feedback activation by RasGTP of the Ras-specific nucleotide exchange factor SOS  1nvw: Structural evidence for feedback activation by RasGTP of the Ras-specific nucleotide exchange factor SOS  1nvx: Structural evidence for feedback activation by RasGTP of the Ras-specific nucleotide exchange factor SOS  1p2s: H-Ras 166 in 50% 2,2,2 triflouroethanol  1p2t: H-Ras 166 in Aqueous mother liquor, RT  1p2u: H-Ras in 50% isopropanol  1p2v: H-RAS 166 in 60 % 1,6 hexanediol  1plj: CRYSTALLOGRAPHIC STUDIES ON P21H-RAS USING SYNCHROTRON LAUE METHOD: IMPROVEMENT OF CRYSTAL QUALITY AND MONITORING OF THE GTPASE REACTION AT DIFFERENT TIME POINTS  1plk: CRYSTALLOGRAPHIC STUDIES ON P21H-RAS USING SYNCHROTRON LAUE METHOD: IMPROVEMENT OF CRYSTAL QUALITY AND MONITORING OF THE GTPASE REACTION AT DIFFERENT TIME POINTS  1pll: CRYSTALLOGRAPHIC STUDIES ON P21H-RAS USING SYNCHROTRON LAUE METHOD: IMPROVEMENT OF CRYSTAL QUALITY AND MONITORING OF THE GTPASE REACTION AT DIFFERENT TIME POINTS  1q21: CRYSTAL STRUCTURES AT 2.2 ANGSTROMS RESOLUTION OF THE CATALYTIC DOMAINS OF NORMAL RAS PROTEIN AND AN ONCOGENIC MUTANT COMPLEXED WITH GSP  1qra: STRUCTURE OF P21RAS IN COMPLEX WITH GTP AT 100 K  1rvd: H-RAS COMPLEXED WITH DIAMINOBENZOPHENONE-BETA,GAMMA-IMIDO-GTP  1wq1: RAS-RASGAP COMPLEX  1xcm: Crystal structure of the GppNHp-bound H-Ras G60A mutant  1xd2: Crystal Structure of a ternary Ras:SOS:Ras*GDP complex  1xj0: Crystal Structure of the GDP-bound form of the RasG60A mutant  1zvq: Structure of the Q61G mutant of Ras in the GDP-bound form  1zw6: Crystal Structure of the GTP-bound form of RasQ61G  221p: THREE-DIMENSIONAL STRUCTURES OF H-RAS P21 MUTANTS: MOLECULAR BASIS FOR THEIR INABILITY TO FUNCTION AS SIGNAL SWITCH MOLECULES  2c5l: STRUCTURE OF PLC EPSILON RAS ASSOCIATION DOMAIN WITH HRAS  2ce2: CRYSTAL STRUCTURE ANALYSIS OF A FLUORESCENT FORM OF H-RAS P21 IN COMPLEX WITH GDP  2cl0: CRYSTAL STRUCTURE ANALYSIS OF A FLUORESCENT FORM OF H-RAS P21 IN COMPLEX WITH GPPNHP  2cl6: CRYSTAL STRUCTURE ANALYSIS OF A FLUORESCENT FORM OF H-RAS P21 IN COMPLEX WITH S-CAGED GTP  2cl7: CRYSTAL STRUCTURE ANALYSIS OF A FLUORESCENT FORM OF H-RAS P21 IN COMPLEX WITH GTP  2clc: CRYSTAL STRUCTURE ANALYSIS OF A FLUORESCENT FORM OF H-RAS P21 IN COMPLEX WITH GTP (2)  2cld: CRYSTAL STRUCTURE ANALYSIS OF A FLUORESCENT FORM OF H-RAS P21 IN COMPLEX WITH GDP (2)  2evw: Crystal structure analysis of a fluorescent form of H-Ras p21 in complex with R-caged GTP  421p: THREE-DIMENSIONAL STRUCTURES OF H-RAS P21 MUTANTS: MOLECULAR BASIS FOR THEIR INABILITY TO FUNCTION AS SIGNAL SWITCH MOLECULES  521p: THREE-DIMENSIONAL STRUCTURES OF H-RAS P21 MUTANTS: MOLECULAR BASIS FOR THEIR INABILITY TO FUNCTION AS SIGNAL SWITCH MOLECULES  5p21: REFINED CRYSTAL STRUCTURE OF THE TRIPHOSPHATE CONFORMATION OF H-RAS P21 AT 1.35 ANGSTROMS RESOLUTION: IMPLICATIONS FOR THE MECHANISM OF GTP HYDROLYSIS  621p: THREE-DIMENSIONAL STRUCTURES OF H-RAS P21 MUTANTS: MOLECULAR BASIS FOR THEIR INABILITY TO FUNCTION AS SIGNAL SWITCH MOLECULES  6q21: MOLECULAR SWITCH FOR SIGNAL TRANSDUCTION: STRUCTURAL DIFFERENCES BETWEEN ACTIVE AND INACTIVE FORMS OF PROTOONCOGENIC RAS PROTEINS  721p: THREE-DIMENSIONAL STRUCTURES OF H-RAS P21 MUTANTS: MOLECULAR BASIS FOR THEIR INABILITY TO FUNCTION AS SIGNAL SWITCH MOLECULES  821p: THREE-DIMENSIONAL STRUCTURES AND PROPERTIES OF A TRANSFORMING AND A NONTRANSFORMING GLYCINE-12 MUTANT OF P21H-RAS |
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