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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oncogenic forms of the p21ras genes have been found in a large variety of human malignancies and tumours induced in animals by chemical carcinogens or irradiation. The active form of the p21 ras proteins is the GTP bound state and oncogenic mutations result in the protein being constitutively in the GTP bound active state. There is evidence to suggest that activating mutations can occur either as initiating steps in carcinogenesis or as later events in the evolution to frank neoplasia. To transduce a signal for proliferation and transformation the active GTP form of p21ras must interact with one or more cellular targets. Genetic experiments suggest that one potential effector molecule is the GTPase activating protein GAP. However, the mechanism by which interaction with GAP results in proliferation and transformation remains to be elucidated.
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PMID:The ras oncogenes. 307 34

Recent work from this laboratory has demonstrated the presence of a structurally and functionally different ornithine decarboxylase (ODC) in mouse epidermal tumors induced by a two-stage protocol involving initiation with 7,12-dimethylbenzanthracene (DMBA) and promotion with 12-O-tetradecanoylphorbol-13-acetate (TPA). In this report, the enzymatic properties of ODC present in DMBA-initiated chrysarobin-promoted papillomas are compared to the enzyme induced by chrysarobin in normal epidermis. Analyses of 13 individual tumor extracts indicated each had an elevated level of ODC activity compared to uninduced normal epidermis. Addition of GTP to the enzyme assay caused a marked stimulation of ODC activity in nine of 13 tumor extracts but had no effect on chrysarobin-induced epidermal ODC. Enzyme kinetic analyses indicated that GTP lowered the atypically high apparent Km values for L-ornithine of the papilloma enzyme to values typical of epidermal ODC. The K 1/2 for GTP activation of papilloma ODC was approximately 7 x 10(-9) M. When a series of nucleotides was tested, only GTP, the non-hydrolysable analog GTP gamma S, dGTP and GDP were capable of significant activation at 1 microM, while other derivatives including GMP, ATP and CTP were less effective. The ability of the tumor enzyme to bind GTP was confirmed by the results of GTP-agarose chromatography, in which the papilloma enzyme (but not chrysarobin-induced epidermal ODC) bound to this affinity column and could be eluted by GTP. While some differences were observed in the properties of ODC from chrysarobin-promoted versus TPA-promoted papillomas, the major conclusion of this study is that both agents cause the appearance of a functionally altered ODC in the majority of papillomas produced by a two-step protocol.
Carcinogenesis 1988 Nov
PMID:Presence of a functionally altered ornithine decarboxylase activity in chrysarobin-promoted mouse epidermal papillomas. 314 Oct 77

Using the human liver cancer DNA transfected NIH/3T3 cell line, the human N-ras oncogene and the over expression of the oncoprotein P21ras was demonstrated, BALB/C mice were immunized. The spleen cells from the immunized mice were fused with SP2/0 myeloma cells. After the HAT medium selection and screening, two hybridoma cell lines, SCI-Oncogema 1 and 2, were established. In the immunoprecipitation test, the molecular weight of the protein reacting to Oncogema 1 was 21,000. This M.W 21,000 protein possessed the capability to bind with GTP, i.e. the character of P21ras. These data indicate that the Oncogema 1 is the monoclonal antibody against P21ras. Using Oncogema 1, specimens from 6 liver cancer patients were studied by immunopathology. With ABC stain, it was observed that the malignant cells in all the samples showed dark staining; the P21ras revealed over expression. Although the staining was heterogeneous, it implied that the ras oncogene was involved in the carcinogenesis of these six samples. No over expression was seen in the normal liver cells even in those around the cancerous lesion. However, dysplastic cells were moderately stained which means that the ras oncogene was activated and P21ras over expressed in these cells. The results suggest that the ras oncogene and P21ras play an important role in the early stage of liver cancer carcinogenesis.
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PMID:[Localization of oncoprotein P21ras in the human liver cancer]. 330 83

The poly (A)-mRNA fraction isolated by chloroform deproteinization of liver polysomes and poly(U)-Sepharose chromatography contains a low molecular weights (congruent to 1000) peptidic fraction. The peptides which we suggested to call deprimerones (1) were extracted with 80% ethanol at pH 9.5; after ethanol evaporation, they were purified on Sephadex G-25 column as a fraction of mol. wt. between 1600 and 600, yielding about 9 mg/mg mRNA. If deproteinization is performed with phenol-chloroform the yield is about 2 mg/mg mRNA. In Novikoff hepatoma the yield of the same preparation is only 2.7 mg/mg mRNA (about 70% decrease). The obtained deprimerones are active in inhibiting transcription of thymus DNA with E. coli RNA polymerase and [3H]-GTP by about 90% at a ratio peptide/DNA = 2. For comparison the deprimerones obtained previously (2) by extraction of deproteinized DNA inhibit transcription only by about 50% at the same peptide/DNA ratio. The results demonstrated a decrease of the poly (A)-mRNA deprimerone level during carcinogenesis and further support the previously demonstrated specific occurrence of deprimerones with poly(A)-mRNA. They remain in accordance with and provide further support for the deprimerone theory of carcinogenesis postulated earlier (1).
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PMID:Poly(A)-mRNA deprimerones in rat liver and Novikoff hepatoma cells. 610 57

gamma-Glutamyl transpeptidase (GTP; EC 2.3.2.2) is an enzyme known to show activity changes during development and carcinogenesis. Its activity was measured in the livers and lungs of female and male rats of different ages, in Morris hepatomas and in experimentally induced pancreatic carcinomas. For comparison purposes, the activity of another peptidase, dipeptidyl aminopeptidase IV (DPAP; EC 3.4.14.1), was assayed in the same tissues. GTP activity was high in fetal liver and hepatomas, but low in adult rat liver, with a marked sex difference, 3 times higher in the female than in the male. In the pancreas, however, the activity of the enzyme was high in the adult but low in the fetus and in pancreatic carcinoma. There were no marked developmental changes or sex differences in pulmonary GTP activities. DPAP levels were low in fetal and neonatal liver and lung, they increased rapidly after birth and showed no sex differences in the adult. In Morris hepatomas and in pancreatic tumors the activity of DPAP was significantly lower than in normal adult liver and pancreas. These results suggest that measurements of GTP (and, to a lesser extent, DPAP) are remarkably suitable for the study of neoplastic cells and tissues.
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PMID:Influence of age, sex and cancer on the activities of gamma-glutamyl transpeptidase and of dipeptidyl aminopeptidase IV in rat tissues. 612 2

Several lines of evidence that indicate that mutation of the Ha-ras oncogene is the initiating event in mouse skin carcinogenesis. Keratinocytes known to possess a mutated Ha-ras have been shown to be resistant to differentiation. Thus, overstimulation of the Ha-ras signaling pathway appears to block normal keratinocyte differentiation, and we hypothesized that for normal keratinocytes to terminally differentiate, the Ha-ras signaling cascade must be turned off. In the present studies, we measured the level and activity state of Ha-ras p21 protein in cultured keratinocytes undergoing calcium-induced differentiation. We have employed Western blot analysis to demonstrate that Ha-ras p21 protein levels remain constant during primary newborn and adult keratinocyte differentiation. The overall level of Ha-ras p21 was higher in immortalized, benign, and malignant mouse keratinocyte cell lines than in normal keratinocytes but did not change within each cell type when subjected to differentiating conditions. The percentage of Ha-ras p21 protein in its active, GTP-bound form also remained unchanged during primary adult keratinocyte differentiation and in immortalized, benign, and malignant keratinocytes subjected to differentiating conditions. Our results indicate that terminal differentiation of primary adult mouse keratinocytes occurred in the presence of constant levels of Ha-ras p21-GTP, suggesting that the Ha-ras signaling pathway may be blocked at a point distal to a step involving the Ha-ras p21 protein itself.
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PMID:Ha-ras p21-GTP levels remain constant during primary keratinocyte differentiation. 766 18

Cholesterol is widely distributed in the animal kingdom and occurs in all cell membranes. Even though the majority of body cholesterol is synthesized by the liver and secreted as circulating lipoproteins, all cells in the body have genomic information for cholesterol biosynthesis. Cholesterol biosynthesis is under feedback regulation, and the cellular and circulating cholesterol levels are tightly regulated at several points, such as the rate limiting enzyme 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase and farnesyl pyrophosphate synthetase and at the low density lipoprotein (LDL) receptor. The cholesterol content and the rate of cholesterol biosynthesis are elevated in proliferating normal tissues and tumors. Cholesterol biosynthesis happens much before DNA synthesis, and inhibiting cholesterol biosynthesis inhibits cell growth, suggesting a linkage between the cholesterol and DNA synthetic pathways. The exact nature of this linkage is not known. However, recent evidence that the farnesyl moiety in the cholesterol biosynthetic pathway is necessary for the activation of G-proteins, and of the ras oncoprotein P21 has provided a probable basis for understanding this linkage, through signal transduction pathways. Thus, farnesylation of G proteins and ras oncoprotein P21 underscores the importance of the cholesterol biosynthetic pathway in cell growth and carcinogenesis. During normal cell growth and differentiation, LDL acts as a negative growth regulator and growth factors as positive signals, the neoplastic cell achieving autocrine growth due to the activation of protooncogens. It is interesting to note that in several types of cancer, the ras gene is mutated; these mutations could increase GTP binding, and lead to an activated p21. The activation of p21 would then be aided by continuous farnesylation due to stimulation of the cholesterol biosynthetic pathway in tumors. The cholesterol biosynthetic pathway, and ras p21 could therefore be used as targets for chemoprevention of cancer.
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PMID:The significance of the cholesterol biosynthetic pathway in cell growth and carcinogenesis (review). 776 99

8-Oxo-7,8-dihydroguanosine triphosphate (8-oxo-dGTP) is formed from the oxidation of GTP in the nucleotide pools of cells during normal cellular metabolism and from exogenous sources. 8-Oxo-dGTP is a potent mutagenic substrate for DNA synthesis causing transversion mutations. In human cells this oxidized base is hydrolyzed to 8-oxo-7,8-dihydroguanosine monophosphate by 8-oxo-7,8-dihydroguanosine triphosphatase (8-oxo-dGTPase) to prevent the misincorporation of 8-oxo-dGTP into cellular DNA. In order to better understand specific human tissue and cell type responses to oxidative stress, we used colorimetric in situ hybridization, with an 8-oxo-dGTPase-specific antisense oligomer probe, to map, for the first time, the cellular distribution of 8-oxo-dGTPase mRNA in tissue sections of normal neonatal foreskin and adult human breast tissues. Paraffin embedded tissue sections were hybridized with a digoxigenin-labeled 39 base oligomer, antisense to 8-oxo-dGTPase cDNA. Hybridization of the probe to cells expressing the 8-oxo-dGTPase gene was visualized following immunodetection with an alkaline phosphatase-conjugated anti-digoxigenin antibody. Following color development, we were able to simultaneously identify tissue architecture and cell types with expression of the 8-oxo-dGTPase gene. There was no hybridization-specific color when sections were 'mock' hybridized, hybridized with a sense probe or treated with RNase. In skin dermis, fibroblasts express high levels of 8-oxo-dGTPAse mRNA. Within the epidermis, a gradient of expression was observed, from high to moderate levels in the replicating basal epithelial cells to undetectable in the non-mitotic suprabasal and granular epithelial cells. In the breast tissue, fibroblasts in the loosely connective tissue and myoepithelial cells expressed high levels of 8-oxo-dGTPase mRNA, while expression in the luminal epithelial cells was not detectable. Our data suggest that expression of 8-oxo-dGTP is heterogenous between cell types within an organ and may help to explain cell type-specific responses to oxidative stress, especially in replicating and potentially replicating cells with low levels of this protective protein.
Carcinogenesis 1995 Feb
PMID:Cell type-specific expression of human 8-oxo-7,8-dihydroguanosine triphosphatase in normal breast and skin tissues in vivo. 785 59

We have established 17 transplantable rat thyroid carcinoma cell lines from primary thyroid tumors of rats induced by N-bis(2-hydroxypropyl)nitrosamine (DHPN) (Cancer Res. (1993) 53, 4408-4412). The present study was designed to evaluate point mutations in the murine c-Ki-ras gene of these carcinoma cell lines. Using PCR amplification and direct sequencing, we found that the activated form of the Ki-ras oncogene was present in 4 (23%) of a total of 17 cell lines, all the Ki-ras gene mutations being GC-->AT transitions. In three of the cell lines, the mutations occurred in codon 12 (GTP-binding domain), and in the remaining one the first nucleotide of codon 63 was affected. Histologically, three of the carcinomas with Ki-ras mutation were diagnosed as well-differentiated carcinomas, and the other as poorly differentiated carcinoma. Mutations of the ras gene are relatively uncommon in tumors of these histological types. From these experimental results, we suggest that the mutation induced by DHPN is due to damage to guanine in cellular DNA. In addition, Ki-ras activation may play an important role in the initiation of thyroid carcinogenesis.
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PMID:Ki-ras oncogene activation in transplantable rat thyroid carcinoma induced by N-bis(2-hydroxypropyl)nitrosamine. 806 17

In recent years green tea has been shown to afford protection against chemical- and photo-carcinogenesis in several animal tumor bioassay systems. It has been suggested that the wide range of anticarcinogenic properties of green tea may be due to the antioxidant effect of epicatechins present therein. In this study, we assessed whether these epicatechin derivatives (ECDs)--namely (-)-epigallocatechin (EGC), (-)-epicatechin gallate (ECG), (-)-epigallocatechin-3-gallate (EGCG) and (-)-epicatechin (EC) inhibit spontaneous and photo-enhanced lipid peroxidation (LPO) in mouse epidermal microsomes. Our data indicate that significant inhibition (significance levels for P, < 0.05 to < 0.0001) was evident by EGCG, EGC and ECG in Fe3+/ADP supported LPO. Interestingly each of these epicatechin derivatives was also effective in inhibiting photo-enhanced LPO generated by incubating epidermal microsomes in the presence of silicon phthalocyanine and 650 nm irradiation. However, at equimolar basis, EGCG, which is also the major constituent in GTP, showed maximum inhibitory effects compared to other ECDs. Taken together, our results provide the direct evidence for the antioxidant property of ECDs, and suggest that such an effect may contribute towards anticarcinogenic (specifically anti-skin tumor) promoting effects of green tea.
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PMID:Inhibition of spontaneous and photo-enhanced lipid peroxidation in mouse epidermal microsomes by epicatechin derivatives from green tea. 818 54


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