Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Protein tyrosine kinase (PTK) activities in methyl nitrosourea (MNU)-induced rat mammary carcinoma has been investigated by using poly (glu: tyr; 4:1) as an exogenous substrate. The PTK activity of the mammary carcinoma was almost equally distributed between the particulate and soluble (cytosolic) fractions at 110,000 X g. The activity of the particulate enzyme was stimulated by non-ionic detergent Triton X-100 by about 2-fold whereas the detergent had no effect on the cytosolic form. More than 60% of the particulate enzyme could be solubilized by 5% Triton X-100. Although, both particulate and cytosolic PTKs catalyzed the phosphorylation of several tyrosine containing synthetic substrates to various degrees, poly (glu: tyr; 4:1) was the best substrate (apparent Km. 0.7 mg/ml). Both forms of enzymes utilized ATP as the phosphoryl group donor, with an apparent Km of 40 microM. Among various divalent cations tested, Co2+, Mn2+ and Mg2+ were able to fulfill the divalent cation requirement of both forms of the PTKs. All these cations exerted biphasic effects on the kinase activities, however, Mg2+ was the most potent cation. Agents such as epidermal growth factor, insulin and platelet derived growth factor which stimulate their respective receptor-PTK activities were without effect on PTK activities of mammary carcinoma. On the other hand, though heparin and quercetin inhibited both enzyme activities in a concentration dependent manner, the particulate form was more sensitive to inhibition than the cytosolic form. These data indicate that MNU-induced rat mammary carcinoma expresses both particulate and cytosolic forms of PTKs and that there are significant differences in the properties of the two forms of PTKs. Differential effects of some agents on mammary carcinoma PTKs suggest that these enzymes may be acutely regulated in vivo and could play an important role in mammary carcinogenesis.
Mol Cell Biochem 1991 Jul 24
PMID:Biochemical characteristics of cytosolic and particulate forms of protein tyrosine kinases from N-methyl-N-nitrosourea (MNU)-induced rat mammary carcinoma. 192 15

Transplacental carcinogenesis represents a good model in which to study the involvement of tissue-specific oncogene activation in carcinogenesis because a single exposure to a carcinogen induces tumors at various sites. We tested tumors of the skin, liver, and lung produced in mice after transplacental 7,12-dimethylbenz[a]-anthracene (DMBA) exposure for possible activation of ras genes. XbaI restriction fragment-length polymorphism analysis has shown that exposure to DMBA in utero may result in appearance of A----T transversion at the second position of codon 61 of Ha-ras oncogene in skin and liver tumors but not in lung tumors. Moreover, DNA samples isolated from spontaneous and DMBA-induced lung and liver tumors were analyzed for mutations at the same position of Ki-ras oncogene using differential hybridization with specific oligonucleotides. Among five spontaneous lung tumors, three cases of A----G transition, and one case of A----T transversion were found, whereas four of ten lung tumors of DMBA-treated animals were positive for A----T mutation. No Ki-ras mutation was detected in one spontaneous and four DMBA-induced hepatomas. In two cases, we revealed Ki-ras A----T mutation in the lung tumor and Ha-ras mutation in the liver tumor taken from the same animal. These results indicate first that DMBA treatment may induce A----T mutation at the second position of codon 61 both in Ha-ras and in Ki-ras and, second, that the role of different activated oncogenes in carcinogenesis may differ, depending on the tissue in which the tumor develops.
Mol Carcinog 1990
PMID:Tissue-specific activating mutations of Ha- and Ki-ras oncogenes in skin, lung, and liver tumors induced in mice following transplacental exposure to DMBA. 197 14

The c-erb B-2/neu gene encodes a cell-surface glycoprotein with extensive homology to, but distinct from, the epidermal growth-factor receptor. In this study, we compared the c-erb B-2/neu gene amplification and expression of tissue specimens obtained from the bladders of normal controls and patients with high-grade transitional cell bladder carcinoma. Southern blot analysis of DNAs from 24 patients and 5 controls showed 2 cases of c-erb B-2/neu gene amplification in patients and none in controls. Western blot analysis demonstrated that c-erb B-2/neu was expressed in 67.6% (23/34) of patient specimens but in none of the controls (0/5). This finding agreed with the result of immunohistochemical staining, which showed that tissue from 74.3% (26/35) of the patients and none of the controls (0/7) showed positive immunofluorescence staining. This is the first report suggesting that c-erb B-2/neu gene amplification may be associated with human bladder carcinogenesis.
Mol Carcinog 1990
PMID:Amplification and expression of the c-erb B-2/neu proto-oncogene in human bladder cancer. 197 77

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.
Mol Carcinog 1991
PMID:Transformation of human breast epithelial cells by c-Ha-ras oncogene. 200 32

Specific, transforming point mutations of ras and alterations in ras expression have been associated with many neoplastic processes, and their presence may be pivotal in neoplastic transformation. Our objective were to evaluate the molecular and genetic alterations of Ki-ras in preneoplastic foci and neoplasms in the lungs of rats that inhaled 239PuO2 aerosols. Histologically classified pulmonary lesions were evaluated by in vitro nucleic acid amplification, oligonucleotide hybridization, and direct nucleic acid sequencing for activating Ki-ras point mutations. We evaluated ras expression in similar lesions using immunohistochemistry and in situ hybridization. Specific Ki-ras point mutations were present in 46% of the radiation-induced malignant neoplasms. Spontaneous pulmonary neoplasms, which are rare in rats, had similar activating mutations and frequencies (40%). We found similar mutation frequencies in radiation-induced adenomas and foci of alveolar epithelial hyperplasia. No mutations were identified in normal lung tissue. Ras expression in hyperplastic lesions and neoplasms was similar to that observed in normal pulmonary epithelia. These findings suggest that Ki-ras activation, not alterations in expression, is an early lesion associated with many radiation-induced, proliferative pulmonary lesions and that this molecular alteration may be an important component of both radiation-induced and spontaneous pulmonary carcinogenesis in the rat.
Mol Carcinog 1991
PMID:The molecular progression of plutonium-239-induced rat lung carcinogenesis: Ki-ras expression and activation. 200 34

The histologic and ultrastructural features of hepatic hemangiopericytoma from a medaka (Oryzias latipes) exposed for 48 hr to 400 mg/liter of diethylnitrosamine at 14 days of age are described. The predominant histologic pattern was of spindle-shaped cells forming numerous whorls around central capillaries, vacuolated areas, or necrotic debris. The predominant cell type was a spindle-shaped cell with oval nuclei, elongated cell processes, and abundant organelles converging upon normal appearing capillaries. Occasionally, however, they converged upon cells swollen with cytoplasmic filaments and/or containing large fenestrated or debris-filled cytoplasmic vacuoles. These features were reminiscent of endothelial cells undergoing intracellular canalization seen in angiogenesis or neovascularization. Individual capillaries were also seen in the mass independent of whorls. It was not clear, as is the case in man, if capillary formation was an integral part of the neoplastic process or a reactive response. Although the liver is an unusual location for hemangiopericytoma in man, many of the cellular features in the fish tumor were similar to the human tumor. The ultrastructural characterization of tumor cells in fish carcinogenesis correlated with histologic patterns of growth will expand our understanding of how fish cells respond when transformed, and augment the development and use of aquatic bioassays for carcinogenesis research.
Exp Mol Pathol 1991 Apr
PMID:Ultrastructure of hepatic hemangiopericytoma in the medaka (Oryzias latipes). 202 37

Previous studies have demonstrated that the mouse c-Harvey ras proto-oncogene (c-Ha-ras) promoter sequences are GC rich and contain several potential transcription factor SP1 binding sites. We investigated the endonuclease hypersensitivity of this region in nuclei in vitro and whole mouse tissues in vivo and identified a very strong, ubiquitous hypersensitive site covering the proximal promoter sequences. Footprint protection studies using nuclear extracts from various cell types including fibroblasts, erythroid cells, and both normal and transformed epithelial cells revealed a consistent protein-binding pattern. Five protein binding sites were observed, four of which correlated with potential SP1 binding sites. Competition experiments using an oligonucleotide corresponding to a consensus SP1 binding site confirmed that these sequences were indeed bound by the SP1 (or SP1-like) trans-acting factor. In addition, no differences were observed between the footprint patterns obtained using extracts from cells of different lineages or between normal and transformed epithelial cells carrying activated ras genes. The controlling elements responsible for differential c-Ha-ras transcription between cell types or at different stages of carcinogenesis therefore probably lie in other regions of the gene.
Mol Carcinog 1991
PMID:Structural analysis of the mouse c-Ha-ras gene promoter. 204 51

Cytochrome P450 is known to cause carcinogen activation and correspondingly increased cancer risk in animal models. In order to determine whether P450 in the colon may be involved in cancer development in the human, the human colon cell line LS174T was examined for the presence of various cytochromes P450. Two isozymes of P450 were identified in the human cell line. Expression of P450IA1 or IA2 was increased by treatment of the cell line with benzanthracene; the induction was demonstrated by an increase in RNA hybridizing to a probe for P450IA1 and by ethoxyresorufin deethylation activity. Western analysis of microsomes isolated from human colon tissue also demonstrated the presence of P450IA1, as well as a form which cross-reacted to an antibody to human P450IIC9. Another isozyme, P450IIE1, was identified by polymerase chain reaction amplification of RNA from LS174T cells. These results underscore the presence of cytochromes P450 in colonic tissue and provide a basis for the involvement of isozyme-specific P450 mediated reactions in carcinogenesis of the colon.
Mol Cell Biochem 1991 Mar 27
PMID:Expression of two cytochromes P450 involved in carcinogen activation in a human colon cell line. 205

BALB/c 3T3 cells were exposed to 7,12-dimethylbenz[a]anthracene (DMBA) and resultant transformed foci were analyzed for the presence of A182----T mutation at codon 61 of Ha-ras (a mutation found in many DMBA-induced animal tumors). None of the 30 independently cloned transformed cell lines contained such a mutation. In order to see whether DMBA is able to induce this mutation in BALB/c 3T3 cells, we developed a method sensitive enough to detect this specific mutation at the frequency of 10(-6). Employing this assay, we found time- and dose-dependent induction by DMBA of Ha-ras A182----T mutation in BALB/c 3T3 cells; for example, 2 wk after exposure to 100 micrograms/mL DMBA, 1.4 in 1 X 10(4) cells contained this specific mutation. On the other hand, other agents that also induce BALB/c 3T3 cell transformation, such as 3-methylcholanthrene (MCA), 12-O-tetradecanoylphorbol-13-acetate (TPA), N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), or ultraviolet light, did not induce the mutation at detectable frequency (less than 10(-6)). These results suggest that DMBA efficiently induces Ha-ras mutation in BALB/c 3T3 cells but that this mutation is not recruited in the process of cell transformation. A hypothesis of carcinogen-specific mutation of Ha-ras gene and its tissue (cell type)-specific recruitment in carcinogenesis is proposed.
Mol Carcinog 1990
PMID:Relationship between chemically induced Ha-ras mutation and transformation of BALB/c 3T3 cells: evidence for chemical-specific activation and cell type-specific recruitment of oncogene in transformation. 211 94

The simian virus 40 (SV40) tumor or T antigen synthesized in transformed or infected cells is highly immunogenic, inducing both antibody and cytotoxic T lymphocyte (CTL) responses. In the C57BL/6 (H-2b) strain of mice the CTL response is directed to discrete sites on T antigen. To date, five CTL recognition sites have been identified using CTL clones, deletion mutants and overlapping synthetic peptides. The CTL sites I, II and III are clustered in the amino-terminal one-third of T antigen, whereas sites IV and V are located in the carboxyl one-third. Using synthetic peptides, the site I has been tentatively assigned to residues 205 to 215 of T antigen and sites II and III map to residues 220 to 233. Site V maps to amino acids 489 to 503. The location of site IV remains undefined but probably falls between amino acids 368 and 511. The CTL sites I, II, III and V are H-2Db-restricted, whereas site IV is H-2Kb-restricted. CTL sites II and III can be distinguished using H-2Db class I mutants which present the same peptide differentially to CTL clones specific for sites II and III. The multiplicity of CTL sites on SV40 T antigen contributes to the overall immunosurveillance in the host against SV40 carcinogenesis. In the event of a loss of a particular site due to mutation or deletion, the remaining CTL sites continue to provide an effective target for CTL-mediated surveillance. Similar events may also contribute toward controlling papovavirus infections in humans.
Mol Biol Med 1990 Feb
PMID:Recognition of simian virus 40 T antigen by cytotoxic T lymphocytes. 215 38


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