Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously reported a stage-specific and sequential overexpression of the c-Ha-ras and c-erbB genes in 7, 12-dimethylbenzanthracene (DMBA)-induced in vivo carcinogenesis in hamster buccal pouch epithelium (HBPE). In this investigation, the immunoreactive protein product of the c-Ha-ras gene (p21 protein) was identified in HBPE cells, specifically in treated tissues and cultured cells established after 3 weeks of DMBA treatment. Microscopic examination did not show any histopathological changes in these tissues. The p21 protein was detected in a few selective cells, which were dispersed away from the more densely populated basal layer. The overexpression of the c-Ha-ras gene was accompanied by a point mutation of A----T in codon 61 (CAA), inducing an amino acid substitution from the wild-type glutamine to leucine in the peptide. The concurrent molecular modifications preceded any detectable histopathological changes. The cellular morphology and orientation in treated HBPE at this early stage was indistinguishable from the control tissue. Yet the genetic alterations, such as the point mutation and overexpression of the gene, were evident at the predysplastic stage. Amplification and overexpression of the second proto-oncogene, c-erbB, and its product, epidermal growth factor receptor (EGFR), were detected in HBPE cells at the later stages of extensive cell proliferation and invasion. By using double antibodies and two immunoreporter systems, we demonstrated overexpression of both c-Ha-ras and c-erbB genes in the same HBPE cells during this chemically induced in vivo carcinogenesis.
 ...
PMID:c-Ha-ras gene mutation and activation precede pathological changes in DMBA-induced in vivo carcinogenesis. 163 Aug 11

We demonstrate in this study that infection with Moloney murine leukemia virus (M-MLV) and exposure to 3-methylcholanthrene (3-MC) can cooperate to transform NIH/3T3 mouse fibroblasts. M-MLV seems to stimulate the expression of c-myc and of a certain major histocompatibility complex (MHC) class I gene. Yet M-MLV infection by itself is insufficient to transform these cells. However, exposure of the infected cells to 3-MC resulted in a rapid cell transformation with concomitant enhancement of c-Ha-ras and H-2K class I MHC gene expression in the transformed cells. No such transformation was observed when uninfected NIH/3T3 cells were similarly treated with this carcinogen. Clones of cells transformed by this combined effect of M-MLV and 3-MC were found to be highly tumorigenic in fully immunocompetent allogeneic BALB/c mice. We provide evidence to suggest that the enhanced expression of the H-2K gene in these transformed cells plays an important role in overcoming the BALB/c allogeneic barrier and allowing tumor growth in these mice.
Carcinogenesis 1990 Dec
PMID:Chemical-retroviral cooperative carcinogenesis and its molecular basis in NIH/3T3 cells. 170 67

We have developed, by microinjection of SV40 DNA into human milk epithelial cells, a new mammary cell line, Hu-MI, which exhibits the phenotype of luminal cells or so-called "breast cancer precursor cells." This cell line retains the phenotype of primary cells as demonstrated by the expression of keratins 18 and 19 and of polymorphic epithelial mucins. However, the cells do not grow in agar after more than 80 passages, nor do they form tumors in nude mice. Established cells contain 2 copies of SV40 DNA integrated into the cellular genome and up to 14 copies of free SV40 DNA. A deletion of the short arm of chromosome 11 (11p15) including the c-Ha-ras and the beta-globin genes was found in the immortalized cells when the DNA from these cells was compared to the DNA from peripheral blood mononuclear cells obtained from the same donor. In addition, this cell line showed a good transfection efficiency for other DNA sequences using classical transfection and selection techniques with a neomycin resistance gene (pKOneo). Selective microinjection of DNA into tumor precursor cells may prove useful for the study of the molecular mechanisms involved in breast carcinogenesis. The possible significance of the loss of 11p13-15 in malignant progression of breast cancer is discussed.
 ...
PMID:Loss of heterozygosity for the short arm of chromosome 11 (11p15) in human milk epithelial cells immortalized by microinjection of SV40 DNA. 170 35

Somatic alterations of the c-Ha-ras gene were examined in 21 Japanese patients with hepatocellular carcinoma. Restriction endonuclease analysis by double digestion with MspI and HpaII revealed that DNAs from two of 21 hepatocellular carcinoma tissues were affected by nucleotide substitution at the twelfth amino acid coding sequence of the c-Ha-ras gene. DNAs from cirrhotic noncancerous liver tissue, but not leukocytes, of one of these patients possessed the mutation, whereas DNAs from noncirrhotic liver tissue and leukocytes of the other patient did not. In one of the nine patients harboring heterozygosity for c-Ha-ras-related BamHI-fragments, the loss of one allele was demonstrated as a somatic change not only in DNA from the tumor tissue but also in DNA from the cirrhotic nontumorous tissue. In two of the 19 patients comparatively examined for digestion patterns of c-Ha-ras locus with HpaII and MspI, extensive methylation was observed as a somatic modification in both DNAs from the tumor and the cirrhotic nontumorous tissues. These results thus indicate that the genetic lesions affecting the c-Ha-ras gene do occur in human hepatocellular carcinoma and probably serve as one of the multiple steps in the process of hepatic carcinogenesis.
 ...
PMID:Point mutation, allelic loss and increased methylation of c-Ha-ras gene in human hepatocellular carcinoma. 184 46

The transforming potential of acrylonitrile epoxide (ANO) was tested in a modified NIH3T3 transfection-transformation assay. This involves a new ras construct obtained by ligating a human c-Ha-ras-1 proto-oncogene to the pSV2neo mammalian vector. The new plasmid was allowed to react with ANO or an established carcinogen in vitro, and the modified ras DNA transfected into NIH 3T3 cells. The transfectants are subjected to triple selections: G418 (neomycin) resistance, low serum growth, and limit dilutions. The end points are scored by cell growth kinetics and monolayer saturation density. In using this protocol, the EJ tumor ras plasmid was the positive control, and anti-benzo[a]pyrene-7,8- dihydrodiol-9,10-epoxide (anti-BPDE) and N-methyl-N-nitrosourea were found to be positive in yielding transformants. Although ANO-modified ras gave rise to two G418R clones, both were scored negative due to their normal growth rate and monolayer density similar to the negative controls. Southern blot analysis of anti-BPDE transformant DNA revealed a fragment of 411 bp, indicating a ras mutation at codon 11 or 12. However, both the ANO clones showed the wild-type band of 355 bp by the same method.
Carcinogenesis 1991 May
PMID:Inactivity of acrylonitrile epoxide to modify a Ha-ras DNA in a non-focus transfection-transformation assay. 190 90

To determine whether the c-Ha-ras oncogene plays a role in the initiation of mammary carcinogenesis, an immortalized human breast epithelial cell line, MCF-10A, was transfected with the plasmid vector pHo6T1 containing the T24 Ha-ras oncogene and the aminoglycoside phosphotransferase gene, which confers resistance to geneticin. Transfected cells exhibited an altered pattern of growth and tridimensional morphology in collagen gel. They also exhibited anchorage-independent growth and loss of requirement for hormones and epidermal growth factor; in addition, they expressed invasiveness and increased collagenolytic activity in an in vitro system and became tumorigenic in irradiated nude mice, all properties indicative of malignant transformation. Transformed cells contained the mutated c-Ha-ras oncogene and expressed the p21 mutated protein. These data indicate that the c-Ha-ras oncogene is capable of inducing malignant phenotypes in immortalized human breast epithelial cells.
 ...
PMID:Transformation of human breast epithelial cells by c-Ha-ras oncogene. 200 32

We have reported earlier that hypomethylated DNA is rapidly induced in the livers of male Fischer rats fed an extremely methyl-deficient diet (MDD). The early effects of dietary methyl deficiency on the expression of several genes in the livers of such animals have now been investigated. Poly(A)+ RNA was isolated from the livers of rats fed MDD or a similar diet supplemented with adequate supplies of choline, methionine, folic acid and vitamin B12 (CSD) for periods ranging from 1 to 4 weeks. The levels of mRNAs for the c-myc and c-fos protooncogenes in livers of rats given either MDD or the liver carcinogen, 2-acetylaminofluorene (AAF), were compared by Northern blot analysis with those in livers of animals given control diets. Both AAF and MDD induced significant elevations in levels of mRNAs specific for these two genes. After 1 week of MDD intake, large increases in the levels of c-myc and c-fos mRNAs and a smaller increase in the levels of c-Ha-ras mRNAs were observed. In contrast, there were marked decreases in the levels of mRNAs for epidermal growth factor receptor and for epidermal growth factor. These effects on mRNA accumulation persisted and were further enhanced during a 4 week period of MDD feeding. The appearance of hypomethylated DNA in the livers of these MDD-fed rats coincided with the observed changes in levels of mRNA for these genes associated with the regulation of cell growth. Increases in levels of mRNA for c-fos, c-Ha-ras and c-myc were correlated with loss of methylation at specific sites within these genes as early as 1 week after the start of MDD feeding. These combined observations are consistent with the hypothesis that methyl-deficient diets are cancer promoting and/or carcinogenic, at least in part, because they induce hypomethylation of DNA with concomitant alterations in the regulation of gene expression.
Carcinogenesis 1991 Jul
PMID:Alterations in expression and methylation of specific genes in livers of rats fed a cancer promoting methyl-deficient diet. 207 Apr 97

UV radiation is a potent DNA damaging agent and a known inducer of skin cancer in experimental animals. There is excellent scientific evidence to indicate that most non-melanoma human skin cancers are induced by repeated exposure to sunlight. UV radiation is unique in that it induces DNA damage that differs from the lesions induced by any other carcinogen. The prevalence of skin cancer on sun-exposed body sites in individuals with the inherited disorder XP suggests that defective repair of UV-induced DNA damage can lead to cancer induction. Carcinogenesis in the skin, as elsewhere, is a multistep process in which a series of genetic and epigenetic events leads to the emergence of a clone of cells that have escaped normal growth control mechanisms. The principal candidates that are involved in these events are oncogenes and tumor suppressor genes. Oncogenes display a positive effect on transformation, whereas tumor suppressor genes have an essentially negative effect, blocking transformation. Activated ras oncogenes have been identified in human skin cancers. In most cases, the mutations in the ras oncogenes have been localized to pyrimidine-rich sequences, which indicates that these sites are probably the targets for UV-induced DNA damage and subsequent mutation and transformation. The finding that activation of ras oncogenes in benign and self-regressing keratoacanthomas in both humans and in animals indicates that they play a role in the early stages of carcinogenesis (Corominas et al., 1989; Kumar et al., 1990). Since cancers do not arise immediately after exposure to physical or chemical carcinogens, ras oncogenes must remain latent for long periods of time. Tumor growth and progression into the more malignant stages may require additional events involving activation of other oncogenes or deletion of growth suppressor genes. In addition, amplification of proto-oncogenes or other genes may also be involved in tumor induction or progression. In contrast to the few studies that implicate the involvement of oncogenes in UV carcinogenesis, the role of tumor suppressor genes in UV carcinogenesis is unknown. Since cancer-prone individuals, particularly XP patients, lack one or more repair pathways, one can speculate that DNA repair enzymes would confer susceptibility to both spontaneous and environmentally induced cancers. Another potential candidate that can function as a tumor suppressor gene is the normal c-Ha-ras gene. Spandidos and Wilkie (1988) have shown that the normal c-Ha-ras gene can suppress transformation induced by the mutated ras gene.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:Molecular mechanisms of ultraviolet radiation carcinogenesis. 208

Experiments were designed to investigate the expression of three cell-cycle-dependent proto-oncogenes in response to two different types of proliferative stimuli: compensatory cell proliferation after partial hepatectomy (PH) or CCl4 and liver hyperplasia induced by the mitogens ethylene dibromide (EDB) and cyproterone acetate (CPA). Steady-state levels of messenger RNAs for c-fos and c-myc were found to be elevated after PH or CCl4 with a maximum increase between 0.5 and 2 h for c-fos and at 2-3 h for c-myc and a rapid decline after 3 h. However, when liver cell proliferation was induced by mitogens, no increase in the expression of c-fos mRNA was observed with both EDB or CPA during the first 24 h. In addition, elevated expression of c-myc was found only in liver hyperplasia induced by EDB, but not with CPA. While the expression of c-myc mRNA and c-fos mRNA was different in the two types of proliferative stimuli, that of c-Ha-ras and c-Ki-ras was similar in all the experimental groups. Cell proliferation monitored by means of incorporation of labelled thymidine into DNA or mitotic index at 24 h following PH, EDB and CPA occurred at a similar extent in all the experimental groups. Our data indicate that the transient and sequential expression of cell-cycle-related genes may vary in response to proliferative stimuli of different nature and suggest that increased expression of cell-cycle-related genes may not be a necessary prerequisite for the entry of the cells into the cell cycle.
Carcinogenesis 1990 May
PMID:Liver hyperplasia is not necessarily associated with increased expression of c-fos and c-myc mRNA. 213 17

Point mutation and activation of c-Ha-ras oncogene was studied at various stages of carcinogenesis in cell lines developed from MNU-treated human pancreas explants. DNAs from normal pancreas and nontumorigenic cell lines showed no transforming activity in NIH 3T3 cells whereas DNA from one of the tumorigenic cell lines transformed NIH 3T3 cells. In this cell line the point mutation was demonstrated to be at codon 12 of c-Ha-ras gene by the loss of an Msp I site. The mutation possibly affected the transcription of c-Ha-ras gene which in turn contributed to the transformation of these cells.
 ...
PMID:MNU-induced point mutation and activation of c-Ha-ras oncogene in cell lines derived from human pancreas explants. 218 1


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>