Disease relevance of Nras

• In Rb1(+/-)Nras(+/-) animals, distant medullary thyroid carcinoma metastases are associated with loss of the remaining wild-type Nras allele [1].
• Loss of one or two Nras alleles is shown to significantly reduce the severity of pituitary tumors arising in Rb1(+/-) animals by enhancing their differentiation [1].
• By contrast, C-cell thyroid adenomas occurring in Rb1(+/-) mice progress to metastatic medullary carcinomas after loss of Nras [1].
• Furthermore, lymphomas of Nras single transgenic animals often expressed higher levels of endogenous Skp2 than tumors of double transgenic mice [2].
• To investigate the relationship between the effects of a pertussis toxin-inhibitable class of G-proteins and the ras family of protooncogenes on cell growth, we isolated multiple cell lines transformed by oncogenic Hras or Nras genes and measured the ability of pertussis toxin to inhibit their growth rate [3].

High impact information on Nras

• These findings suggest that the loss of the proto-oncogene Nras in certain cellular contexts can promote malignant tumor progression [1].
• Nras loss induces metastatic conversion of Rb1-deficient neuroendocrine thyroid tumor [1].
• R-ras has at least six exons, with the position of the first intron conserved relative to the Drosophila ras64B and Dictyostelium ras genes; there is no similarity in the exon-intron structure of the R-ras gene and of the mammalian H-, K-, and N-ras proto-oncogenes [4].
• The active N-ras oncogene coexists with altered versions of the myc oncogene in the HL-60 and AW Ramos human tumors [5].
• The biological effects of ras oncogene activation in B cells were studied by using amphotropic retroviral vectors to introduce H- or N-ras oncogenes into human B lymphoblasts immortalized by Epstein-Barr virus [6].

Chemical compound and disease context of Nras

• Furthermore, the FPTase inhibitor (FTI) L-744,832 causes tumor regression in mouse mammary tumor virus (MMTV)-v-Ha-ras transgenic mice and tumor stasis in MMTV-N-ras mice [7].
• In order to compare the molecular pathways of carcinogenesis in humans and animals, Sprague-Dawley rats were exposed to vinyl chloride and hepatic tumors, including two hepatocellular carcinomas and five liver angiosarcomas, were investigated for mutations at codons 12, 13 and 61 of the Ha-ras, Ki-ras and N-ras genes [8].
• MATERIALS AND METHODS: K- and N-ras mutations in thymic lymphomas that arose in X-ray-irradiated and N-ethyl-N-nitrosourea (ENU)-treated mice of susceptible C57BL/6, rather resistant C3H and their hybrid B6C3F1 were analysed by polymerase chain reaction-single-strand conformation polymorphism and subsequent DNA sequencing [9].
• To examine K-, H-, or N-ras and p53 gene mutations in mouse endometrial carcinogenesis induced by N-methyl-N-nitrosourea and 17 beta-estradiol, we performed polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) in 13 adenocarcinomas and 11 other preneoplastic lesions [10].
• Establishment and characterization of a melanoma cell line from a xeroderma pigmentosum patient: activation of N-ras at a potential pyrimidine dimer site [11].

Biological context of Nras

• K-ras is an essential gene in the mouse with partial functional overlap with N-ras [12].
• Most animals lacking N-ras function and heterozygous for the K-ras mutation exhibit abnormal hematopoietic development and die between days 10 and 12 of embryogenesis [12].
• The improved differentiation of skeletal muscle in Rb(-/-); N-ras(-/-) embryos occurs despite evidence of deregulated proliferation and apoptosis, as seen in Rb-deficient animals [13].
• Targeted genomic disruption of H-ras and N-ras, individually or in combination, reveals the dispensability of both loci for mouse growth and development [14].
• Four different human tissue-derived cell lines, each previously shown to express either a Ha-, Ki-, or N-ras-activated oncogene, were fused in four different paired combinations [15].

Anatomical context of Nras

• Rb(-/-); N-ras(-/-) skeletal muscle has normal fiber density, myotube length and thickness, in contrast to Rb-deficient embryos [13].
• NIH 3T3 transfection assays and Southern blot analysis of DNA from transformed NIH 3T3 cells confirmed the presence of a dominant activated N-ras gene [8].
• Tumor cell lines bearing H-ras or N-ras mutations were among the most sensitive of the cell lines tested, with responses observed at nanomolar concentrations of R115777 [16].
• Four protooncogenes (c-fos, c-abl, N-ras, and c-raf) were expressed at low levels in both steps of erythroleukemia. c-fos and c-abl RNAs were barely detectable in normal erythroid cells [17].
• All cases of non-neoplastic mesothelium and the majority of the malignant mesotheliomas (78 per cent) showed cytoplasmic and often submembranous immunoreactivity in more than 50 per cent of the cells with both the pan-ras and N-ras antibody [18].

Associations of Nras with chemical compounds

• This mutation results in the incorporation of leucine instead of glutamine at residue 61 of the N-ras gene product, p21 [19].
• In addition, we found that N-nitrosodiethylamine, 4-aminoazobenzene, and N-hydroxy-2-acetylaminofluorene all caused G to T transversions in the N-ras gene (codons 12 or 13) [20].
• The expression of these genes is driven by a glucocorticoid-responsive promoter and the addition of dexamethasone resulted in a dramatic induction (10-20-fold) of H- or N-ras mRNA, peaking 4 h after hormone addition [21].
• The products of the Ha-, Ki-, and N-ras proto-oncogenes comprise a family of 21 kDa guanine nucleotide-binding proteins which play a crucial role in growth factor signal transduction and in the control of cellular proliferation and differentiation [22].
• The MMTV-LTR ras-incorporated cells treated with either dexamethasone or TCDD grew in soft agar to form colonies (anchorage independent growth), while nontreated cells did not, indicating profound cellular changes due to activation of N-ras by these two agents [23].

Physical interactions of Nras

• Myb binding sites within the N-ras promoter repress transcription [24].

Regulatory relationships of Nras

• The K-ras gene was preferentially activated over the N-ras gene (approximately 2:1) whether the inducing agent was radiation or the chemical N-nitrosomethylurea [25].
• Ha-ras and N-ras regulate MAPK activity by distinct mechanisms in vivo [26].
• Mutated N-ras upregulates Bcl-2 in human melanoma in vitro and in SCID mice [27].
• Toward understanding the mechanism of action of Krev-1 protein, we constructed a series of point mutants of Krev-1 cDNA and tested their biological activities in DT cells and HT1080 human fibrosarcoma cells harboring the activated N-ras gene [28].
• c-myc amplification coexistent with activating N-ras point mutation in the biphenotypic leukemic cell line RED-3 [29].

Other interactions of Nras

• A c-Ha-ras gene was shown to be activated in a myeloid leukaemia and a recently identified member of the 'ras' gene family, N-ras, was found to be activated in a lung carcinoma [30].
• Primary transfectant DNAs were analyzed by Southern blot hybridization with DNA probes homologous to c-Ha-ras, c-Ki-ras, and N-ras oncogenes [31].
• We show that deletion of N-ras rescues a unique subset of the developmental defects associated with nullizygosity of Rb, resulting in a significant extension of life span [13].
• In addition, we have excluded Csf1 and Nras as candidates for both loci [32].
• This upregulation of mRNA expression paralleled an increase in neurofibromin and N-ras levels, but no change in the relative abundance of the isoforms containing exon 23a or exon 48a was observed during in vitro myoblast differentiation [33].

Analytical, diagnostic and therapeutic context of Nras

• Northern blot analysis demonstrated equivalent steady-state levels of N-ras transcripts in Hep G2 cells and normal human liver [19].
• While G35-->A or G35-->T transition detected by PCR and dot-blot hybridization was confirmed by sequencing, the mutations identified similarly at codon 61 in either the Ha- or N-ras oncogenes could not be verified by sequencing of PCR-amplified products subcloned into plasmid vectors [34].
• Dissection of the mouse N-ras gene upstream regulatory sequences and identification of the promoter and a negative regulatory element [35].
• Molecular cloning and chromosome assignment of murine N-ras [36].
• Inactivation of the murine N-ras gene by gene targeting [37].

References