Disease relevance of Hras1

• In total, mutations of the Trp53, Hras1 and/or Catnb genes were identified in 15 out of 17 1,3-butadiene-induced mammary adenocarcinomas [1].
• H-ras mutation is normally a hallmark of DMBA-TPA-induced skin tumors, but 70% of carcinomas from Pten+/- mice do not exhibit this mutation, and in all cases have lost the wild-type Pten allele [2].
• Rat embryo fibroblasts transformed with the HPV-16 E7 gene and the activated c-H-ras gene fall into two distinct phenotypic classes [3].
• Finally, expression of mutated forms of p21 ras did not abrogate the sensitivity of phospholipase C activation to pertussis toxin [4].
• Molecular probes for the oncogenes of Rous sarcoma virus (v-src), avian myeloblastosis virus (v-myb), Kirsten murine sarcoma virus (v-Ki-ras), and Harvey murine sarcoma virus (v-Ha-ras) were hybridized to the DNA from mouse-Chinese hamster somatic cell hybrids [5].

Psychiatry related information on Hras1

• Thus, the aim of this study was to investigate in mice, the relationships between the ras-dependent protein kinase ERK and MDMA-induced reinforcement using the conditioned place preference (CPP) and locomotor activity measurements [6].
• The latency period between the time of infection and appearance of the lesions suggested that secondary alterations in addition to activated ras were necessary for neoplasms to develop [7].
• Transformation of established murine fibroblasts with an activated cellular Harvey-ras oncogene or the polyoma virus middle T gene increases cell permissiveness to parvovirus minute-virus-of-mice [8].

High impact information on Hras1

• Their embryo fibroblasts (MEFs) do not senesce and are transformed by oncogenic Ha-ras alone [9].
• Here we report that embryonic fibroblasts (EFs) from mice with a null mutation in the IRF-1 gene (IRF-1-/- mice) can be transformed by expression of an activated c-Ha-ras oncogene [10].
• Furthermore, expression of the c-Ha-ras oncogene causes wild-type but not IRF-1-/- EFs to undergo apoptosis when combined with a block to cell proliferation or treated by anticancer drugs or ionizing radiation [10].
• These results permit us to propose zeta PKC as a critical step downstream of p21ras in mitogenic signal transduction [11].
• Introduction of the catalytic region of GAP into this line resulted in morphological reversion and lower in vivo GTP binding by endogenous p21ras [12].

Chemical compound and disease context of Hras1

• The farnesyltransferase inhibitor L-744,832 selectively blocks the transformed phenotype of cultured cells expressing a mutated H-ras gene and induces dramatic regression of mammary and salivary carcinomas in mouse mammary tumor virus (MMTV)-v-Ha-ras transgenic mice [13].
• Early changes in recognition sites, presumed to indicate altered methylation status of DNA cytosine and/or guanine mutations, were seen using c-DNA probes for DMT, c-Ha-ras and c-jun; in the p53 tumor suppressor gene alteration of such sites was a late event relevant to appearance of liver adenomas and hepatocellular carcinomas [14].
• We previously reported p53 mutations to be frequent (greater than 70%), whereas both H-ras mutations and microsatellite instability (MSI) were infrequent (about 10%), in urinary bladder carcinomas (UBCs) and their metastatic foci in the N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN)-induced mouse urothelial carcinogenesis model [15].
• Although the oncogenic allele H-ras(V12) is present in only approximately 6% of ovarian cancers, physiologically activated H-ras protein is commonly detected in human ovarian cancer, presumably because of an increase in upstream signals from tyrosine kinase growth factor receptors such as Her-2/neu, despite the lack of a Ras mutation [16].
• H-ras mutations were identified in 26% (5/19) of spontaneous, 50% (7/14) of benzene-, and 33% (4/12) of ethylene oxide-induced carcinomas [17].

Biological context of Hras1

• In contrast, Hras1-mutant Wnt1-induced tumors consistently remained oncogene dependent [18].
• Significant amplification is restricted to the chromosome with the Hras1 mutation [19].
• We have already shown that c-Ha-ras and the tumor promoter TPA (12-o-tetradecanoyl phorbol-13-acetate) can activate a transcriptional enhancer [20].
• These results provide genetic evidence that in NIH-3T3 cells, ras p21 is involved in signal transduction mediated by CSF-1R [21].
• Loss of transcription factor IRF-1 affects tumor susceptibility in mice carrying the Ha-ras transgene or nullizygosity for p53 [22].

Anatomical context of Hras1

• Soft agar colony formation by NIH 3T3 cells transformed by ras oncogenes is not affected by anti-p185 antibody treatment [23].
• Ha-ras and c-myc oncogene expression interferes with morphological and functional differentiation of mammary epithelial cells in single and double transgenic mice [24].
• CONCLUSIONS: These results suggest that the activation of the p21ras and Py-MT/pp60c-src oncogenic pathways are critical effectors at different stages of colorectal carcinogenesis and in Caco-2 cells interferes with the program of enterocyte differentiation [25].
• Ki-ras activation was detected in one primary rat liver tumor, and Ha-ras activation was detected in the cell line transformed in vitro with activated aflatoxin B1 [26].
• The postmicrosomal fraction of the extract from NIH 3T3 and BALB/c 3T3 cells stimulated the hydrolysis of GTP bound to H-ras gene product p21 by severalfold [27].

Associations of Hras1 with chemical compounds

• Neither class of transformants expressing Ki-ras or Ha-ras displayed a significant basal activity of polyphosphoinositide-specific phospholipase C, measured either in serum-starved cells or during exponential growth in the presence of growth factors of the tyrosine kinase family (EGF, FGF, insulin) [4].
• To confirm that these aberrations occurred within the first cell cycle after mutant Ha-ras induction, the cells were arrested in G1 phase by serum depletion and, subsequently, released by administration of isopropyl beta-D-thiogalactoside or serum [28].
• The NIH 3T3 cells used in this study contained mutant p53 genes and carried a selectively inducible activated (EJ) Ha-ras transgene under the control of bacterial lactose regulatory elements [28].
• In contrast, proto-oncogenic forms of N-ras or H-ras had no apparent effects on the ability of C2 cells to differentiate [29].
• A similar reduction in pp130 phosphorylation and reversion of morphology by herbimycin A were observed in v-src- and c-Ha-ras-transformed cells [30].
• Basal tone of the H-ras(-/-) IAS was significantly higher and resistant to relaxation by Y 27632, compared with the H-ras(+/+) IAS [31].

Physical interactions of Hras1

• In comparison with introduction of v-myc alone or both H-ras and v-myc oncogene, introduction of H-ras alone resulted in a loss of [125I]EGF binding activity to the cell surface EGF receptor [32].
• Utilising a dominant negative mutant of p21ras we demonstrate that both insulin-induced Stat3 DNA-binding and also transactivation do not require p21ras [33].
• Because c-Jun is the most potent transactivator in the AP-1 complex and is elevated in Ha-ras-transformed cells, in which c-Fos is downregulated, we focused on it as a potential target. c-Jun could convert input from an oncogenic signalling cascade into changes in gene expression [34].
• Cellular ras genes encode a family of membrane-associated proteins (p21ras) that bind guanine nucleotide and possess a low intrinsic GTPase activity [35].
• Previous studies have shown that the aberrant p21ras proteins are potential tumor-specific antigens in that CD4+ class II major histocompatibility complex-restricted T cells specific for the mutated segment of various oncogenic p21ras proteins can be elicited by immunization in vivo with synthetic peptides corresponding to the mutated segment [36].

Regulatory relationships of Hras1

• We report that in T24 H-ras-transformed NIH 3T3 cells enhanced transcription contributes to the increased expression of OPN [37].
• Loss of oncogenic H-ras-induced cell cycle arrest and p38 mitogen-activated protein kinase activation by disruption of Gadd45a [38].
• The protein product of this gene, p53ERTM, is expressed in cells constitutively but is not functional unless associated with tamoxifen or 4-hydroxytamoxifen. p53ERTM was introduced into p53-deficient mouse embryo fibroblasts (MEFs) expressing the E1A and T24 H-ras oncogenes [39].
• Regulation of epidermal growth factor receptor by activated H-ras and V-myc oncogenes in mouse Balb/3T3 cells: possible roles of AP-1 [32].
• TGF-beta1-induced fibroblast proliferation is smaller in H-ras(-/-)/N-ras(-/-) than in H-ras(+/-)/N-ras(+/-) fibroblasts [40].

Other interactions of Hras1

• 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 [41].
• Activation of extracellular signal-regulated kinase, ERK2, by p21ras oncoprotein [42].
• Mouse cellular homologs c-src, c-Ki-ras, c-Ha-ras, and c-myb segregated concordantly with chromosomes 2, 6, 7, and 10, respectively [5].
• HC11 cells expressing the neuT and activated c-erbB-2 genes synthesized beta-casein in response to lactogenic hormones, whereas those expressing the Ha-ras or transforming growth factor-alpha oncogenes were no longer able to respond to the lactogenic hormones [43].
• The region of interaction was mapped to amino acids 71 to 96, and the central portion (amino acids 71 to 124) of Gadd45a was required for p38 MAPK activation in the presence of H-ras [38].

Analytical, diagnostic and therapeutic context of Hras1

• In immunoblotting experiments, the affinity purified mAb, ras(53-69)Leu61, reacts specifically with the purified, bacterially produced rasLeu61 protein and does not react with bacterially produced normal H-ras protein [44].
• Oral administration b.i.d. of R115777 to nude mice bearing s.c. tumors at doses ranging from 6.25-100 mg/kg inhibited the growth of tumors bearing mutant H-ras, mutant K-ras, and wild-type ras genes [45].
• In one case, restriction enzyme analysis demonstrated the presence of a mutation in codon 12 of the activated Ha-ras oncogene [46].
• RT-PCR analysis also showed much lower levels of EGF receptor gene expression in H-ras transfectants compared to that of parental untransformed cells (Balb-Neo1), v-myc and H-ras/v-myc transfectants [32].
• To clarify the role of the H-Ras in vivo, we generated H-ras null mutant mice by gene targeting [47].

References