Neuroblastoma RAS viral oncogene homolog explained

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.^{[1] [2]} 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 2 kb and 4.3 kb. The difference between the two transcripts is a simple extension through the termination site of the 2 kb transcript. The N-Ras gene consists of seven exons (-I, I, II, III, IV, V, VI). The smaller 2 kb transcript contains the VIa exon, and the larger 4.3 kb 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.^[3]

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^[3] e.g. melanoma.

As a drug target

Binimetinib (MEK162) has had a phase III clinical trial for NRAS Q61 mutant melanoma.^[4]

Further reading

• McCormick F . Ras-related proteins in signal transduction and growth control. . Mol. Reprod. Dev. . 42 . 4 . 500–6 . 1996 . 8607982 . 10.1002/mrd.1080420419 . 6507743 .
• van Elsas A, Scheibenbogen C, van der Minne C, etal . UV-induced N-ras mutations are T-cell targets in human melanoma. . Melanoma Res. . 7 . S107–13 . 1998 . Suppl 2 . 9578425 . 10.1097/00008390-199708001-00017. 19219505 .
• Dracopoli NC, Meisler MH . 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 . 1990 . 1692298 . 10.1016/0888-7543(90)90523-W . 2027.42/28584 . free .
• Yuasa Y, Kamiyama T, Kato M, etal . Transforming genes from familial adenomatous polyposis patient cells detected by a tumorigenicity assay. . Oncogene . 5 . 4 . 589–96 . 1990 . 1970154 .
• Hancock JF, Magee AI, Childs JE, Marshall CJ . All ras proteins are polyisoprenylated but only some are palmitoylated. . Cell . 57 . 7 . 1167–77 . 1989 . 2661017 . 10.1016/0092-8674(89)90054-8 . 19292550 .
• Hall A, Brown R . Human N-ras: cDNA cloning and gene structure. . Nucleic Acids Res. . 13 . 14 . 5255–68 . 1985 . 2991860 . 10.1093/nar/13.14.5255 . 321863 .
• Hirai H, Tanaka S, Azuma M, etal . Transforming genes in human leukemia cells. . Blood . 66 . 6 . 1371–8 . 1986 . 10.1182/blood.V66.6.1371.1371 . 2998510 . free .
• Neri A, Knowles DM, Greco A, etal . Analysis of RAS oncogene mutations in human lymphoid malignancies. . Proc. Natl. Acad. Sci. U.S.A. . 85 . 23 . 9268–72 . 1988 . 3057505 . 10.1073/pnas.85.23.9268 . 282720 . 1988PNAS...85.9268N . free .
• Nitta N, Ochiai M, Nagao M, Sugimura T . 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 . 1987 . 3102434 .
• Raybaud F, Noguchi T, Marics I, etal . Detection of a low frequency of activated ras genes in human melanomas using a tumorigenicity assay. . Cancer Res. . 48 . 4 . 950–3 . 1988 . 3276402 .
• Hirai H, Kobayashi Y, Mano H, etal . A point mutation at codon 13 of the N-ras oncogene in myelodysplastic syndrome. . Nature . 327 . 6121 . 430–2 . 1987 . 3295562 . 10.1038/327430a0 . 1987Natur.327..430H . 4270769 .
• Gambke C, Hall A, Moroni C . 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 . 1985 . 3856237 . 10.1073/pnas.82.3.879 . 397150 . 1985PNAS...82..879G . free .
• Padua RA, Barrass NC, Currie GA . Activation of N-ras in a human melanoma cell line. . Mol. Cell. Biol. . 5 . 3 . 582–5 . 1985 . 10.1128/mcb.5.3.582 . 3887133 . 366752 .
• Brown R, Marshall CJ, Pennie SG, Hall A . Mechanism of activation of an N-ras gene in the human fibrosarcoma cell line HT1080. . EMBO J. . 3 . 6 . 1321–6 . 1984 . 10.1002/j.1460-2075.1984.tb01970.x . 6086315 . 557516 .
• Yuasa Y, Gol RA, Chang A, etal . 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 . 1984 . 6587382 . 10.1073/pnas.81.12.3670 . 345280 . 1984PNAS...81.3670Y . free .
• Taparowsky E, Shimizu K, Goldfarb M, Wigler M . Structure and activation of the human N-ras gene. . Cell . 34 . 2 . 581–6 . 1983 . 6616621 . 10.1016/0092-8674(83)90390-2 . 39787991 .
• Mitchell EL, Jones D, White GR, etal . 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 . 1995 . 7789166 . 10.1159/000134028 .
• Kodaki T, Woscholski R, Hallberg B, etal . The activation of phosphatidylinositol 3-kinase by Ras . Curr. Biol. . 4 . 9 . 798–806 . 1995 . 7820549 . 10.1016/S0960-9822(00)00177-9 . 20836474 .
• Rodriguez-Viciana P, Warne PH, Vanhaesebroeck B, etal . Activation of phosphoinositide 3-kinase by interaction with Ras and by point mutation . EMBO J. . 15 . 10 . 2442–51 . 1996 . 10.1002/j.1460-2075.1996.tb00602.x . 8665852 . 450176 .

External links

• GeneReviews/NCBI/NIH/UW entry on Noonan syndrome

Notes and References

1. Marshall CJ, Hall A, Weiss RA . A transforming gene present in human sarcoma cell lines . Nature . 299 . 5879 . 171–3 . September 1982 . 6287287 . 10.1038/299171a0 . 1982Natur.299..171M . 4342747 .
2. Shimizu K, Goldfarb M, Perucho M, Wigler M . Isolation and preliminary characterization of the transforming gene of a human neuroblastoma cell line . PNAS . 80 . 2 . 383–7 . January 1983 . 6300838 . 10.1073/pnas.80.2.383. 393381 . 1983PNAS...80..383S . free .
3. Web site: Entrez Gene: NRAS neuroblastoma RAS viral (v-ras) oncogene homolog.
4. https://clinicaltrials.gov/ct2/show/NCT01763164 Study Comparing the Efficacy of MEK162 Versus Dacarbazine in Unresectable or Metastatic NRAS Mutation-positive Melanoma