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)

Our most recent work [Hibino et al. (1995) Cancer Lett., 88, 49-55] has shown that the selective binding affinities of highly repetitive DNA components for a nuclear scaffold protein from rat ascites hepatoma cells (P230) depend on the degree of sequence-directed bending of the helix axis. In the present experiment, this protein has been highly purified and isolated by a series of column chromatographic procedures to migrate as a single band to a molecular weight position of 230 kd on a SDS-polyacrylamide gel. A filter binding assay showed that the binding of a repetitive AT-rich component (369 bp XmnI fragment) from the hepatoma nucleus, which has a strongly bent overall structure, to isolated P230 is based on a cooperative mode of interaction. Distamycin A, which binds specifically to AT-rich DNA, removed the bend in the XmnI fragment and inhibited binding to this protein. These results suggest that AT-rich regions in highly repetitive DNA cause bending of the helix axis to be recognized by nuclear scaffold protein(s). Moreover, it has been shown that the nuclear scaffold fraction from rat liver or an actively growing hepatocyte cell line (Ac2F cells) does not contain P230, but does have a repetitive bent DNA binding protein (P130), which has an apparent molecular weight of 130 kd. In addition, the immunoblot analysis showed that mouse anti-P130 antiserum reacts with P230. Thus, the results in the present study imply that there is some difference in the higher order structure of the nuclear DNA attachment region between rat liver or actively growing hepatocytes and the hepatoma, although P230 appears to be immunochemically similar to P130.
Carcinogenesis 1997 Apr
PMID:Purification and characterization of a DNA binding protein in a nuclear scaffold fraction from rat ascites hepatoma cells. 911 Dec 4

The tumour suppressor gene p53 is expressed in response to DNA-damage; its protein product blocks cells in the G1-phase of the cell cycle. This gives cells additional time to repair their DNA-damage. However, it may trigger apoptosis if damage is too high. Loss of p53 function appears to be an important step in carcinogenesis because 50% of human tumours have lost functional p53. In order to study the role of p53 in experimental hepatocarcinogenesis, we determined the expression of p53 in rat liver in response to various hepatocarcinogenic and hepatotoxic compounds. Administration of hepatocarcinogenic compounds increased p53 protein levels in the liver as detected by immunoprecipitation followed by SDS-PAGE and Western blotting with ECL-detection. The hepatocarcinogens included N-hydroxy-2-acetylaminofluorene, aflatoxin B1, and diethylnitrosamine. Their structural analogues N-hydroxy-4-acetylaminobiphenyl and ethyl methane-sulphonate which are not hepatocarcinogenic, did not induce p53. Also, two hepatotoxic compounds (carbon tetrachloride, D-galactosamine) did not induce p53. Other compounds that induced p53 in the rat liver were 2-aminofluorene (administered by drinking water for two weeks) and tris-(2,3-dibromopropyl)phosphate. Benzo[a]pyrene did not induce p53. N-Hydroxy-2-acetylaminofluorene, aflatoxin B1, and diethylnitrosamine are potent hepatic tumour promoters. At the same time, they induce p53 protein expression and inhibit proliferation of normal hepatocytes. Because this is not observed with non-hepatocarcinogenic analogues, it suggests an involvement of p53 expression in hepatic tumour promotion. A possible mechanism is discussed.
Carcinogenesis 1997 May
PMID:p53 protein expression by hepatocarcinogens in the rat liver and its potential role in mitoinhibition of normal hepatocytes as a mechanism of hepatic tumour promotion. 916 91

In vitro studies of endometrial carcinogenesis have been hampered by dedifferentiation of the cells in culture. Using the endometrial carcinoma cell line HEC-1B(L), we aimed to establish and characterize culture conditions that preserve a more differentiated state of the tumor cells. HEC-1B(L) cells grown in a serum-free defined medium on plastic (PL/SFDM) on top of a reconstituted basement membrane (Matrigel, MG/SFDM) or in a thick layer of Matrigel showed pronounced morphological differentiation as compared with HEC-1B(L) cells cultured on plastic in a medium containing serum (PL/10% FCS). Features of differentiation included cuboidal to columnar cell shape and an increase of rough endoplastic reticulum in Matrigel cultures. Gene expression of HEC-1B(L) cells was studied by metabolic [35S]methionine labeling and SDS-gel electrophoresis. HEC-1B(L) cells cultured in the presence of Matrigel showed two additional secretory proteins approximately 31 kD and 77 kD in size. rt-PCR was used to screen cell cultures for the presence of estrogen receptor, progesterone receptor, and lactoferrin-mRNA, genes typically expressed by normal endometrial epithelium. We found no expression of the estrogen receptor or progesterone receptor. Lactoferrin-mRNA was present under all culture conditions tested. Our results suggest a regulatory role of the extracellular matrix for the differentiation of the HEC-1B(L) cell line.
 ...
PMID:Basement membrane induced differentiation of HEC-1B(L) endometrial adenocarcinoma cells affects both morphology and gene expression. 921 25

Cytochrome P4501A1 (CYP1A1) has been implicated in the conversion of numerous polycyclic aromatic hydrocarbons into electrophilic species capable of binding covalently to DNA and has therefore been postulated to be involved in the initiation of carcinogenesis. The expression of CYP1A1 protein appears not to be constitutive, but is readily inducible by aryl hydrocarbon (Ah) receptor ligands in a majority of tissues of experimental animals, especially the liver. To date, there is conflicting evidence for the expression or inducibility of CYP1A1 protein in human liver. In this present study, we report the detection of CYP1A1 in all 20 human liver microsomal samples tested by standard western immunoblotting with chemiluminescent detection using a specific monoclonal antibody (mAb 1-12-3) directed against a marine fish (scup) cytochrome P450E. mAb 1-12-3 has been shown previously to specifically recognize CYP1A1 in mammals. This system consistently demonstrated a detection sensitivity as low as 0.01-0.025 pmol CYP1A1 per lane. In the samples where CYP1A1 protein levels were quantitated, CYP1A1 ranged from approximately 0.4 to 5 pmol CYP1A1/mg microsomal protein. Additionally, the inducibility of CYP1A1 protein was demonstrated by incubating precision-cut human liver slices in dynamic organ culture for up to 96 h in the presence of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The specificity of mAb 1-12-3 was tested using several purified human and rat cytochrome P450s to ensure that the protein being detected was CYP1A1. mAb 1-12-3 did not cross-react with human CYP1A2 or CYP3A4 or rat CYP1B1, but did strongly recognize CYP1A1. However, there was a very weak cross-reactivity of mAb 1-12-3 with human CYP2E1, approximately 75-fold less compared with CYP1A1. In order to confirm CYP1A1 as the immunoreactive protein detected in human liver, microsomal samples were subjected to two-dimensional electrophoresis involving isoelectric focusing followed by SDS-PAGE and immunoblotting. Utilizing mAb 1-12-3, the human liver microsomal samples displayed an immunoblotting profile matching that obtained from a microsomal preparation from a AHH-1 TK+/- cell line expressing solely human CYP1A1 and differing from the profile obtained using a polyclonal antibody directed against CYP2E1 and cells expressing CYP2E1. Furthermore, mAb 1-12-3 recognized only one protein of identical mobility on the two-dimensional blots from human liver microsomes and AHH-1 TK+/- cells expressing CYP1A1, while displaying no reaction to cells expressing only CYP2E1. In conclusion, CYP1A1 appears to be expressed in human liver at low levels and is inducible upon exposure to TCDD.
Carcinogenesis 1998 Aug
PMID:Detection of CYP1A1 protein in human liver and induction by TCDD in precision-cut liver slices incubated in dynamic organ culture. 974 30

Formaldehyde (FA) is a genotoxic substance, induces tumors in the nasal epithelium of rats, and is suspected to be a human carcinogen. As a primary DNA lesion, FA induces DNA-protein crosslinks (DPC) and the formation of DPC has been used as a measure of exposure for risk estimation. However, the significance of DPC for mutagenesis and carcinogenesis is at present poorly understood. We therefore performed comparative investigations on the induction of DPC and other genetic endpoints by FA in V79 Chinese hamster cells. The amount of DPC was comparatively determined with the K-SDS assay and the comet assay. Both tests gave similar results but the comet assay was much foster and easier to perform. Our results show that FA significantly induces DPC, sister-chromatid exchanges, and micronuclei in the same range of concentrations, parallel to the induction of cytotoxicity (relative cloning efficiency). In contrast, treatment of V79 cells with FA did not induce gene mutations in the HPRT test even after variations of the treatment protocol. Our results indicate that FA-induced DPC seem to be related to cytotoxicity and clastogenicity but do not lead to the formation of gene mutations in mammalian cells. It is suggested that FA-induced DPC do not cause gene mutations that are involved in FA-induced carcinogenesis.
 ...
PMID:Significance of formaldehyde-induced DNA-protein crosslinks for mutagenesis. 981 41

Human cytochrome P450 1A2 is one of the major cytochrome P450s in human liver. It is known to be capable of activating a number of carcinogens such as arylamines and heterocyclic amines. In order to develop the new bacterial mutagenicity test system with human P450, a full length of human P450 1A2 cDNA inserted into pCW bacterial expression vector was introduced to Escherichia coli WP2 uvrA strain which is a well-known E. coli strain for bacterial reverse mutagenicity assay. Expressed human P450 1A2 showed typical P450 hemoprotein spectra. Maximum expression was achieved at 48 hrs after incubating at 30 degrees C in terrific broth containing ampicillin, IPTG and other supplements. High level expression of P 450 1A2 in E. coli WP2 uvrA membranes was determined in SDS-PAGE. The well-known mutagens 2-aminoanthracene and MelQ increased the revertant colonies of E. coli WP2 uvrA expressing human P450 1A2 without an exogenous rat hepatic post-mitochondrial supernatant (S9 fraction) in a dose-dependent manner. The results show that the functional expression of human P450 in bacterial mutagenicity tester strain will provide a useful tool for studying the mechanism of the mutagenesis and carcinogenesis of new drugs and environmental chemicals.
 ...
PMID:Expression of recombinant human cytochrome P450 1A2 in Escherichia coli bacterial mutagenicity tester strain. 987 48

Dimethyl methylphosphonate (DMMP) is a widely used chemical. Diethyl ethylphosphonate (DEEP) has been proposed as a replacement for DMMP in several applications. A long-term carcinogenesis study with DMMP in rats and mice showed a significant increase in the incidence of kidney tumors after 2 years of exposure in male but not in female rats and both sexes of mice. DMMP is not genotoxic. Due to these findings, a role of alpha(2u)-globulin accumulation in organ-specific tumorigenicity may be possible. alpha(2u)-Globulin is a low-molecular-weight protein synthesized in male rats under androgen control. Several male rat specific renal carcinogens have been shown to bind to alpha(2u)-globulin and to impair the renal degradation of this protein. This impairment results in alpha(2u)-globulin accumulation in the kidney, lysosomal overload, cell death, cell proliferation, and finally, renal tumor induction. To further characterize the toxicology of DMMP and DEEP, we investigated the biotransformation of these compounds and their ability to induce alpha(2u)-globulin accumulation in kidney. Biotransformation of both DMMP and DEEP were studied in male and female rats after single oral doses of 50 and 100 mg/kg. 31P-NMR and GC/MS showed that unchanged DMMP was excreted with urine; methyl phosphonate was identified as the only metabolite in urine. Unchanged DEEP was also excreted with urine; in addition, ethyl ethylphosphonate and ethylphosphonate were urinary metabolites. The majority of the applied dose of both compounds was recovered in urine within 24 h indicating rapid absorption and excretion. No sex-differences in rates of formation or excretion of metabolites were seen. To investigate alpha(2u)-globulin accumulation in the kidney after DMMP and DEEP, male and female Fischer-344 rats were administered DMMP or DEEP daily for five consecutive days by gavage. DMMP doses were 500- and 1,000-mg/kg body weight (bw); due to marked toxicity, daily DEEP dose of 50 and 100 mg/kg had to be used. Control rats received corn oil only and positive controls received five doses of 500-mg/kg bw trimethylpentane (TMP). Relative kidney weights were increased in male rats dosed with DMMP, DEEP, and TMP. alpha(2u)-Globulin in kidney cytosol was separated and quantified by capillary electrophoresis and by SDS-PAGE and Western blotting. In DMMP-, DEEP-, and TMP-treated rats, dose-dependent increases in the alpha(2u)-globulin content were observed by both methods in male, but not female rats. The increase of alpha(2u)-globulin accumulation was accompanied by the formation of protein droplets in the proximal tubules of male rats. These data demonstrate that the sex specific increase in kidney tumors by DMMP in male rats may be due to alpha(2u)-globulin accumulation and that similar toxic effects are to be expected from DEEP.
 ...
PMID:Biotransformation and male rat-specific renal toxicity of diethyl ethyl- and dimethyl methylphosphonate. 1065 17

We previously identified a non-p53, p53-responsive DNA element (p53RE)-binding protein named NBP, functionally analogous to p53, from human cervical carcinoma Hela cells. Here we report a biochemical study demonstrating that this activity is the recently cloned p53 analog p63. NBP was purified through conventional and DNA affinity chromatography to apparent homogeneity with a prominent polypeptide migrating in between the 43 and 68 kDa positions on a SDS gel. This polypeptide immunoreacted with monoclonal anti-p63 but not anti-p53 or anti-p73 antibodies. Also, NBP co-purified with p63 through each step of fractionation, as detected with anti-p63 antibodies. DNA-protein complexes formed with purified NBP and p53RE-containing oligomers derived from the p21(waf1) promoter were supershifted by anti-p63 but not anti-p53 antibodies. Thus, these results demonstrate that NBP is encoded by the p53 homolog p63 gene.
Carcinogenesis 2001 Feb
PMID:NBP is the p53 homolog p63. 1118 41

High concentrations of non steroidal antiinflammatory drugs (NSAIDs) exert preventive effects against carcinogenesis. Their molecular mechanism of action remains to be elucidated. Based on previous reports with salicylate, we have made the hypothesis that various NSAIDs can activate the mitogen-activated protein kinases (MAPK). Moreover, we tested the idea that NSAIDs act by increasing the effects of oxidative stress. We report that in human colorectal carcinoma cells NSAIDs stimulated the three families of MAPK, extracellular regulated kinases, c-Jun N-terminal kinases, p38 MAPK and that this stimulation is prevented by N-acetyl cysteine. In cultured astrocytes, a biological system less sensitive to oxidative stress, we show that a short treatment by NSAIDs strongly activated the three MAP kinases in the presence of H(2)O(2). A 25 microM H(2)O(2), unable to stimulate by itself the MAP kinases, promote an almost complete activation of MAP kinases in the presence of NSAIDs. The activation of MAP kinases by H(2)O(2) and NSAIDs was suppressed by quinone reductase inhibitors, suggesting that "redox cycling" was involved in the activation mechanisms of MAP kinases by H(2)O(2) and NSAIDs. The mobility on SDS-PAGE of the apoptosis signal-regulating kinase, which activates C-Jun N-terminal kinases and p38 MAPK cascades, was reduced by H(2)O(2) and NSAIDs, suggesting, that H(2)O(2) and NSAIDs activated apoptosis signal-regulating kinase by increasing its state of phosphorylation. In conclusion, we demonstrate that various NSAIDs can activate the three families of MAP kinases and that this activation depends on the presence of reactive oxygenated species. These results give a new insight into the mechanism of the action of NSAIDs.
 ...
PMID:Role of redox status on the activation of mitogen-activated protein kinase cascades by NSAIDs. 1184 90

In the present study we investigated production of the peptide of retroviral origin in patients with various types of leukemia. For this purpose the high affinity rabbit antibodies were generated against the synthetic peptide representing the "immunosuppressive motif" within the envelope protein of human endogenous retrovirus type C. The presence of this peptide was identified only in sera of the patients with chronic myelo- and/or promonocytic leukemia at acute phase. Furthermore, the appearance of this protein correlated with agranulocytosis. SDS-PAGE profile revealed the serum protein recognized by Ab that had MW of 88 kDa. However, in bone marrow cells, the same Ab bound 66 kDa peptide, and low molecular weight peptide, INF-agr;, as well. It was determined that 88 kDa protein was a highly glycosylated version of 66 kDa protein. Staining blood cells and bone marrow cells with FITC-labelled specific monoclonal antibodies demonstrated that CD34(+) cells produced this peptide. The appearance of this peptide in sera of patients with myeloid leukemia was considered as unfavorable prognosis since it was followed with lethality in 50% of cases. Thus, besides potential involvement of endogenous retroviral products in carcinogenesis, they may be considered as a factor of immunosuppression.
 ...
PMID:Production of Peptide of Retroviral Origin in Sera of Patients with Chronic Myeloid Leukemia at Acute Phase. 1268 93


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