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PubMed1991

cAMP and cell sorting control the spatial expression of a developmentally essential cell-type-specific ras gene in Dictyostelium.

The Dictyostelium ras gene (Dd-ras) is expressed at a low level in vegetative cells, is not expressed between the onset of development and aggregation, and is then re-expressed in the multicellular aggregate stages from the distal, now cAMP-responsive, promoter and from two more proximal promoters. Expression of activated Dd-ras (G12----T12) (Reymond et al. 1986) results in an abnormal developmental phenotype with the formation of aggregates having multiple tips and an inhibition of further development. In this report we investigate the spatial expression of Dd-ras by fusing the 5'-flanking region to the Escherichia coli lacZ gene and by staining aggregates for beta-galactosidase (beta-gal) activity. We show that fusions using 5'-flanking sequences that include all promoters are expressed in approximately 10-20% of the cells randomly scattered within the early aggregate. Our data indicate that these beta-gal-expressing cells migrate to newly formed tips of aggregates and localize in the region that becomes the prestalk zone. Staining is also seen in the very posterior of the organism. The anterior staining appears to be specific for the prestalk A population, and beta-gal activity is subsequently present in stalk cells as developmental proceeds. When only the two more proximal promoters are used to drive lacZ expression, localized staining is seen in the anterior prestalk region, although it is weaker than with the construct carrying all promoters. Moreover, staining is not seen in the posterior domain in the first finger stage, suggesting differences in the spatial expression from the different promoters. Staining is also observed in some cells within the prespore region, which could be anterior-like cells. The pattern of Dd-ras/lacZ staining during tip formation suggests a directed, spiral pattern of cell migration, possibly in response to the proposed spiral gradient of cAMP within the developing aggregate. The pattern of Dd-ras is consistent with the abnormal developmental phenotype caused by expressing an activated Dd-ras Thr12 gene and suggests an essential role for Dd-ras in controlling spatial differentiation.

Amino Acid Sequence↗

PubMed1985

The involvement of activated ras genes in determining the transformed phenotype.

Activated ras oncogenes have been identified in a wide range of tumours. All examples of ras gene activation in tumours so far result from amino acid substitution at Gly12 or Gln61. To learn more about how mutations in ras genes lead to transformation, we have analysed transforming growth factor production in NIH/3T3 cells transformed by each of the three ras genes. These results show that the transformed phenotype of these cells results from a combination of the presence of the mutant ras protein and TGF alpha production. In a second series of experiments we have shown that the mutation of a ras gene in a tumour cell line can lead to tumour progression towards a more aggressive phenotype.

Animals↗

PubMed2004

The role of ras genes in the neoplasmic transformation in animals.

We can distinguish three kinds of ras genes i.e. H-ras, K-ras and N-ras, which are rated as ras-protooncogenes. The point mutations within ras genes are frequently detected in human malignancies and in experimentally induced tumors in animals. The aim of this article is to review briefly current research on the role and the frequency of ras gene mutational activation in naturally occurring animal tumors. The present studies show that the mutational activation of ras genes at the hot-spot loci in codons 12, 13 and 61 is apparently rare and does not perform an important role in the pathogenesis of naturally occurring tumors in animals. However, we cannot be sure if the mutational activation of ras genes occurs most often, but in other functional areas of these genes, or if there are other mechanisms involved in their activation.

Animals↗

PubMed1989

Multiple Harvey-ras genes in the bovine genome.

Three different Harvey-ras (Ha-ras) genes have been identified in the bovine genome by screening a lambda phage-bovine DNA library with the ras gene of the Harvey murine sarcoma virus. The genes have been characterized by hybridization and heteroduplex analysis with both the viral and human Ha-ras genes. Based on heteroduplex mapping, the putative direction of transcription and the approximate position of the coding regions of the bovine genes were established. Two genes, bovine Ha-ras 1 and 2, both show an arrangement of exons and introns typical of c-Ha-ras genes. However, they are distinct entities as they have different nucleotide sequences and physical maps, and heteroduplexes between them contain a region of non-homology upstream of exon 1. The third gene, c-Ha-ras 3, does not contain introns and is a pseudogene, analogous to human c-Ha-ras 2. The nucleotide sequence of both Ha-ras 1 and Ha-ras 2 has been determined and shows that Ha-ras 1 encodes a bona fide ras protein, whereas Ha-ras 2 has diverged considerably from a recognizably functional sequence.

Amino Acid Sequence↗

PubMed1997

K-ras gene mutations in normal colorectal tissues from K-ras mutation-positive colorectal cancer patients.

K-ras gene mutations have been reported as early events in colorectal tumorigenesis, but their role in tumor initiation and development is still unclear. To analyze and compare K-ras mutational patterns between colorectal tissues at different stages of tumor progression in individual patients, 65 colorectal tissue samples, including carcinoma, adenoma, histologically normal mucosa, submucosal muscularis propria, and histologically normal mucosa distant from tumor, were obtained from 13 patients with colorectal cancer. In addition, normal mucosal tissues obtained from four normal individuals were analyzed. Each of the 13 tumors was shown previously to harbor a mutation in either codon 12 or 13 of the K-ras gene by direct sequencing. These tissues were reanalyzed, using the recently established mutant allele enrichment + denaturing gradient gel electrophoresis method, which can detect one mutant allele in 10(4)-10(5) normal alleles, thus allowing for the analysis of infrequent cells bearing mutations against the background of wild-type cells. No K-ras codon 12 mutation was detected by this method in the histologically normal mucosal tissues sampled at the margin of resection distant from the tumor or in those obtained from four normal individuals. On the other hand, these mutations were detected in 9 of 10 adenoma and 6 of 10 mucosa samples from 10 patients with known K-ras codon 12 mutations, and also in 2 of 3 carcinoma, 2 of 3 adenoma, and 1 of 3 mucosa samples obtained from 3 patients with known K-ras codon 13 mutations. Thus, K-ras codon 12 mutations were found to occur with a high frequency (53.8%) in histologically normal mucosa adjacent to tumors of patients with K-ras mutation-positive colorectal cancer, suggesting that they may be useful biomarkers for early detection of colorectal cancer. Furthermore, multiple K-ras mutations were found in tissues of nearly half of the 13 patients, indicating that distinct evolutionary subclones may be involved in the development of tumor in some patients with colorectal cancer.

Adenoma↗

PubMed1994

Far less frequent mutations in ras genes than in the p53 gene in skin tumors of xeroderma pigmentosum patients.

Mutations in Ha-ras, Ki-ras, and N-ras genes in squamous and basal cell carcinomas in patients with xeroderma pigmentosum (XP) were examined by the polymerase chain reaction followed by single-strand conformation polymorphism analysis and direct base sequencing. No mutation was detected in codons 12, 13, and 61 of the ras genes in XP skin tumors. This was in contrast with previous findings of a high frequency of mutation in the p53 gene in skin tumors in XP patients. A novel mutation in codon 6 of the Ki-ras gene was detected in a squamous cell carcinoma. The mutation was a C-->T transition at a dipyrimidine (5'-CT) sequence and could have been produced by solar ultraviolet light. The mutated ras gene did not have the ability to transform NIH/3T3 cells. In three tumors, multiple base substitutions were detected in exon 1 of the Ki-ras and N-ras genes. These results and our previous work on p53 gene mutations suggest that mutations in ras genes are far less frequent than in the p53 gene in the skin tumors in XP patients and that ras genes are less important in skin tumorigenesis in XP patients than is the p53 gene.

3T3 Cells↗

PubMedDate not supplied

ras gene mutations in human endometrial carcinoma.

The purpose of this study was to assess the extent of involvement of the ras oncogene activation by point mutations in endometrial carcinoma in the Greek population. The PCR technique was employed, followed by RFLP analysis to identify the point mutations in codon 12 of the K-ras, H-ras and N-ras genes. K-ras gene point mutations were detected in 8 of the 55 cases (15%) of primary endometrial carcinoma, H-ras in 4 (7.3%), while no mutations were found for the N-ras gene. No correlation was found between the presence of ras gene mutations and the clinicopathological parameters, or patient survival. The only association found was between H-ras mutations and the FIGO stage of the tumor (Fisher's exact test, p = 0.011). These results indicate a possible role of ras gene activation in a small subset of endometrial carcinomas.

Carcinoma↗

PubMed1988

Induction of ras gene expression by homologous aggregation factor in cells from the sponge Geodia cydonium.

Northern blot data as well as immunocytochemical and immunoblotting experiments indicate that the sponge Geodia cydonium contains the ras gene (or ras-related gene). The ras gene transcript has a size of 1.5 kilobases and the ras gene product has an Mr of 23,000-26,000. While dissociated G. cydonium cells lack ras gene product, ras gene expression can be induced by incubating the cells with the cell-binding fragment of the homologous aggregation factor. Maximal expression was observed 10-15 h after addition of the fragment. The sponge ras protein was partially purified by immunoprecipitation and bound GTP with a dissociation constant of 1.8 x 10(-6) M. It was found to be associated with the cell membrane. Autoradiographic studies revealed that the ras protein binds to the plasma membrane-associated anti-aggregation receptor and thereby mediates the mitogenic response, caused by the homologous lectin. It is hypothesized that sponges are provided in addition to the aggregation factor-caused and protein kinase C-mediated pathway with a second mechanism of transduction of mitotic signals, the lectin-caused and ras-mediated signaling.

Animals↗

PubMed2002

Preferential DNA damage and poor repair determine ras gene mutational hotspot in human cancer.

BACKGROUND: Mutations in ras genes are commonly found in human cancers and in animal models. Although mutations at codons 12, 13, and 61 of H-, N- and K-ras genes can activate their oncogenic function, mutations at codon 12 of K-ras are the most common mutations found among the three ras genes in human cancers. To investigate whether codon 12 of human K-ras is especially susceptible to carcinogens and/or whether carcinogen-DNA adducts at this codon are repaired less efficiently, we examined tobacco smoke carcinogen-induced DNA damage in normal human bronchial epithelial and fibroblast cells. METHODS: We used the UvrABC nuclease incision method in combination with ligation-mediated polymerase chain reaction to map the distribution of DNA adducts induced by benzo[a]pyrene diol epoxide (BPDE) and other bulky carcinogens within exons 1 and 2 in H-ras, N-ras, and K-ras. We also analyzed BPDE-DNA adduct repair efficiency in these three genes using the same method. RESULTS: Codons 12 and 14 of the K-ras gene were hotspots for carcinogen-DNA adduct formation, with little and no adduct formation at codons 13 and 61, respectively. The BPDE-DNA adducts formed at codon 14 were repaired almost twice as quickly as those formed at codon 12. There was some BPDE-DNA adduct formation at codons 12 of H-ras and N-ras, but this codon was not a hotspot. Furthermore, no substantial difference in repair rates between codon 12 and the other codons analyzed (codons 3 and 18) was observed in either the H-ras or N-ras genes. CONCLUSION: These findings link the human cancer mutational hotspot at codon 12 of K-ras to preferential DNA damage and poor repair.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗

PubMed1993

Possible role of activated ras genes in human esophageal carcinogenesis.

Activation by point mutation of the H-, K- and N-ras genes is found in many tumors. However, no such mutation has yet been found in human esophageal carcinomas from various parts of the world. We have confirmed the absence of mutation at codons 12, 13 and 61 of K- and N-ras and at codons 12 and 61 of H-ras in 25 primary tumors obtained in France. In contrast, among 7 human esophageal carcinoma cell lines (TE1, TE2, TE3, TE8, TE9, TE10, TE13) with different degrees of tumorigenicity in nude mice, 3 highly tumorigenic lines (TE1, TE2 and TE8) exhibited activation of ras oncogenes; 2 showed a G35 to A35 transition of K-ras gene and one a H-ras G35 to T35 transversion. Since these cell lines had been established from tumors of Japanese patients from Sendai, we examined 3 primary esophageal tumors from Tokyo and 19 from Sendai, including the primary tumors from which the TE cell lines had been derived. No ras mutation was detected, which suggests that the ras gene mutations in the TE cell lines are either due to their long-term culture or that only a small portion of the original tumors contained such mutations. In order to directly examine the effect of ras gene mutation, one of the non-tumorigenic cell lines, TE13, was transfected with a plasmid coding for a mutated H-ras gene (G35 to T35). Transfected clones expressing high levels of mutated ras gene were able to induce tumors in nude mice. Thus, although no primary human esophageal tumor contained mutated ras genes, our studies do not exclude a significant role of mutated ras genes in cell proliferation and malignant transformation of human esophageal cells.

Adult↗

PubMed1997

Dominant transformation by mutated human ras genes in vitro requires more than 100 times higher expression than is observed in cancers.

The gene-mutation-cancer hypothesis holds that mutated cellular protooncogenes, such as point-mutated proto-ras, "play a dominant part in cancer," because they are sufficient to transform transfected mouse cell lines in vitro [Alberts, B., Bray, D., Lewis, J., Raff, M., Roberts, K. & Watson, J. D. (1994) Molecular Biology of the Cell (Garland, New York)]. However, in cells transformed in vitro mutated human ras genes are expressed more than 100-fold than in the cancers from which they are isolated. In view of the discrepancy between the very low levels of ras transcription in cancers and the very high levels in cells transformed in vitro, we have investigated the minimal level of human ras expression for transformation in vitro. Using point-mutated human ras genes recombined with different promoters from either human metallothionein-IIA or human fibronectin or from retroviruses we found dominant in vitro transformation of the mouse C3H cell line only with ras genes linked to viral promoters. These ras genes were expressed more than 120-fold higher than are native ras genes of C3H cells. The copy number of transfected ras genes ranged from 2-6 in our system. In addition, nondominant transformation was observed in a small percentage (2-7%) of C3H cells transfected with ras genes that are expressed less than 20 times higher than native C3H ras genes. Because over 90% of cells expressing ras at this moderately enhanced level were untransformed, transformation must follow either a nondominant ras mechanism or a non-ras mechanism. We conclude that the mutated, but normally expressed, ras genes found in human and animal cancers are not likely to "play a dominant part in cancer." The conclusion that mutated ras genes are not sufficient or dominant for cancer is directly supported by recent discoveries of mutated ras in normal animals, and in benign human tissue, "which has little potential to progress" [Jen, J., Powell, S. M., Papadopoulos, N., Smith, K. J., Hamilton, S. R., Vogelstein, B. & Kinzler, K. W. (1994) Cancer Res. 54, 5523-5526]. Even the view that mutated ras is necessary for cancer is hard to reconcile with (i) otherwise indistinguishable cancers with and without ras mutations, (ii) metastases of the same human cancers with and without ras mutations, (iii) retroviral ras genes that are oncogenic without point mutations, and (iv) human tumor cells having spontaneously lost ras mutation but not tumorigencity.

Animals↗

PubMed1986

The cloning and characterization of a RAS gene from Schizosaccharomyces pombe.

We have cloned and determined the complete nucleotide sequence of a RAS gene from the yeast Schizosaccharomyces pombe (SP-RAS). The putative RAS protein of 214 amino acids is encoded by two noncontiguous reading frames separated by an intron of 86 bp. The SP-RAS gene product shares extensive homology with the proteins of the Saccharomyces cerevisiae (SC), Dictyostelium, Drosophila, and human RAS genes in its N-terminal region but not in its C-terminal region. The extended C-terminal regions found in the SC-RAS genes have no counterpart in the SP-RAS gene. Thus the RAS genes of these two yeasts are structurally quite distinct. The SP-RAS sequence was expressed in vivo.

Base Sequence↗

PubMed1986

Harvey ras genes transform without mutant codons, apparently activated by truncation of a 5' exon (exon -1).

The hypothesis is tested that the ras gene of Harvey sarcoma virus (Ha-SV) and the proto-ras DNAs from certain tumor cells derive transforming function from specific codons in which they differ from normal proto-ras genes. Molecularly cloned Harvey proviral vectors carrying viral ras, normal rat proto-ras, and recombinant ras genes in which the virus-specific ras codons 12 and 59 were replaced by proto-ras equivalents each transformed aneuploid mouse 3T3 cells after latent periods that ranged from 4 to 10 days. Viruses with or without virus-specific ras codons all transformed diploid rat cells in 3-5 days equally well. However, in the absence of virus replication, mutant codons were beneficial for transforming function. Deletion of non-ras regions of Ha-SV did not affect transforming function. We conclude that specific ras codons are not necessary for transforming function. Comparisons of the ras sequences of Ha-SV, BALB SV, and Rasheed SV with sequences of proto-ras genes from rat and man revealed an upstream proto-ras exon, termed exon -1. The 3' end of this exon is present in all three viruses and in a ras pseudogene of the rat. Since ras genes transform without mutation and since exon -1 is truncated in viral ras genes and all transforming proto-ras DNAs of the Harvey and the Kirsten ras family, we propose that ras genes are activated by truncation of exon -1 either via viral transduction or artificially via cloning and transfection. The proposal implies that untruncated proto-ras genes with point mutations may not be cellular cancer genes.

Animals↗

PubMed1991

Loss of growth control by TGF-beta occurs at a late stage of mouse skin carcinogenesis and is independent of ras gene activation.

The relationship between the expression of a mutant ras gene in epithelial cells and loss of responsiveness to the negative effects of transforming growth factor beta (TGF-beta) is presently unclear. We have investigated this question using a series of cell lines derived from benign and malignant mouse skin tumours which express mutant forms of the H-ras gene. Immortalised, non-tumorigenic mouse epidermal cells respond to TGF-beta by cessation of growth, whereas in a series of malignant carcinoma lines the response was substantially reduced. Introduction of a mutant H-ras gene into the immortalised cells did not lead to any appreciable change in TGF-beta responsiveness, suggesting that initiation of carcinogenesis by ras mutation does not directly alter growth control by this pathway. Of two non-tumorigenic papilloma lines tested which had mutant H-ras genes, one retained complete sensitivity to TGF-beta, whereas the other showed a similar response to carcinomas. We conclude that growth control by TGF-beta is lost at a relatively late stage of carcinogenesis in this system, and is independent of ras gene activation.

Animals↗

PubMed2007

Relevance of Ras gene mutations in the context of the molecular heterogeneity of multiple myeloma.

Ras gene mutations are a recurrent genetic lesion in multiple myeloma (MM). Here, we report a mutation analysis of N- and K-Ras genes in purified plasma cell populations from a panel of 81 newly diagnosed MM patients stratified according to the most frequent genetic and molecular features associated with the neoplasia. Ras gene mutations, mostly involving the N-Ras gene, were detected in 20% of the patients. Ras mutations did not correlate with the presence of chromosome 13q deletion, trisomy of chromosome 11, 1q amplification or hyperdiploidy. In addition, despite an appreciable association with tumours overexpressing Cyclin D1, Ras mutations did not correlate at significant levels with any of the proposed groups in the TC classification, based on the presence of the major IgH chromosomal translocations and expression of Cyclin D genes. Finally, transcription analyses revealed the presence of differentially expressed transcripts in human multiple myeloma cell lines carrying the Ras gene mutations but not in primary tumours. Overall, these data suggest that Ras gene mutations are not likely to represent a master lesion in MM but its relevance needs to be considered in the context of other genetic abnormalities.

Adult↗

PubMed1989

[Detection of ras gene mutations of pancreatic tumors by polymerase chain reaction and direct sequencing method].

Ras genes (H-,K-,N-ras) are converted to active oncogenes by point mutations occurring in either codon 12, 13 or 61. We analyzed 19 pancreatic tumors (formalin fixed paraffin embedded tissue) of these codons by a method to directly sequence nucleotides around codons 12/13 and 61 of the three ras genes, using polymerase chain reaction and direct sequencing method. Of 19 pancreatic tumors, all 17 duct cell carcinomas involving 2 mucous producing pancreatic cancers had point mutations of the K-ras codon 12, but 2 islet cell tumors had ano point mutation around codons 12, 13, 61 of the three ras genes. Extremely high incidence of ras gene mutation may be relevant to certain pathogenesis of pancreatic cancers.

Base Sequence↗

PubMed1999

Genetic alterations in Ki-ras and Ha-ras genes in juvenile nasopharyngeal angiofibromas and head and neck cancer.

CONTEXT: Ras gene mutations have been associated to a wide range of human solid tumors. Members of the ras gene family (Ki-ras, Ha-ras and N-ras) are structurally related and code for a protein (p21) known to play an important role in the regulation of normal signal transduction and cell growth. The frequency of ras mutations is different from one type of tumor to another, suggesting that point mutations might be carcinogen-specific. OBJECTIVES: To study the occurrence of Ki-ras and Ha-ras mutations. We also studied the relative level of Ha-ras mRNA in 32 of the head and neck tumors. DESIGN: Case series. SETTING: University referral unit. PARTICIPANTS: 60 head and neck tumors and in 28 Juvenile Nasopharyngeal Angiofibromas (JNA). DIAGNOSTIC TEST: Using PCR-SSCP we examined the occurrence of Ki-ras and Ha-ras mutations. The relative level of Ha-ras mRNA was examined by Northern blot analysis. RESULTS: None of the head and neck tumors or JNA samples showed evidence of mutations within codons 12, 13, 59 and 61 of Ki-ras or Ha-ras genes. However, 17 (53%) of the tumors where gene expression could be examined exhibited increased levels of Ha-ras mRNA compared with the normal tissue derived from the same patient. CONCLUSIONS: Our results demonstrate for the first time that mutations of Ki-ras and Ha-ras genes are not associated with the development of JNA and confirm previous reports indicating that activating ras mutations are absent or rarely involved in head and neck tumors from western world patients. Furthermore, our findings suggest that overexpression of Ha-ras, rather than mutations, might be an important factor in the development and progression of head and neck tumors.

Adult↗

PubMed1991

Clinical application of ras gene mutation for diagnosis of pancreatic adenocarcinoma.

Most pancreatic adenocarcinomas are known to have ras gene (oncogene) mutations. The site of the mutations is localized in codon 12 of K-ras gene. Such high incidence and localization of the ras gene mutations have not been observed in any other human malignancies. Polymerase chain reaction and direct sequencing method enabled us to analyze DNA sequence around codon 12 of K-ras gene in small quantities of specimens obtained from needle biopsies and aspirate samples for pathological diagnosis. All the materials obtained from 12 patients with pancreatic adenocarcinoma showed the mutations, whereas those obtained from 6 patients with chronic pancreatitis showed no mutations. In several cases using the mutations of K-ras gene as a marker, this analysis supplemented conventional pathology and cytology in making the diagnosis of pancreatic adenocarcinoma. The analysis of ras-gene mutations was useful for the clinical diagnosis of pancreatic adenocarcinoma.

Adenocarcinoma↗