Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P50583 (asymmetrical)
 12,197 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The molecular structure and conformation of the cis-5,6-dihydrodiol of 7,12-dimethylbenz[a]anthracene has been determined by an X-ray crystallographic analysis. The compound crystallizes in the space group P21/a with cell dimensions a equals 17.799(6), b equals 33.211(8), c equals 5.241(1) A, beta equals 91.88(2)degrees. There are two molecules, designated A and B in the asymmetrical unit, that are not related to each other by crystallographic symmetry. Their conformations are almost identical, and there are no significant differences in their bond lengths or angles. In both molecules the 5-hydroxyl group is equatorial while the 6-hydroxyl group is axial. This conformation is probably forced by steric hindrance between the hydroxyl group, 0-6, and the hydrogen atoms of the 7-methyl group. The molecules pack in the crystal by forming hydrogen bonds between the hydroxyl groups of adjacent molecules, A with A, B, with B, and A with B. The ring system of the cis-5,6-dihydrodiol is much more buckled than is that in 7,12-dimethylbenz[a]anthracene itself. The angle between the two outermost rings is 36 degrees, the deviation from planarity being primarily a consequence of the partial saturation in the ring containing the two hydroxyl groups. Extrapolation of these results to other dihydrodiol derivatives of carcinogenic hydrocarbons permits some predictions of preferred molecular geometry. Thus, the 8,9-dihydrodiol-10,11-epoxide of 7,12-dimethylbenz]a[anthracene, analogous to the biologically active 7,8-dihydrodiol-9,10-epoxide of benzo]a[pyrene, a mutagen that is believed to be an active intermediate in carcinogenesis by benzo]a[pyrene, should probably exist preferentially in a conformation bearing the8-hydroxyl group in the axial orientation.
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PMID:Molecular structure of the K-region cis-dihydrodiol of 7,12-dimethylbenz[a]anthracene. 40 8

Epithelial cells lose their usual polarization during carcinogenesis. Although most malignant tumours are of epithelial origin little is known about ion channels in carcinoma cells. Previously, we observed that migration of transformed Madin-Darby canine kidney (MDCK-F) cells depended on oscillating K+ channel activity. In the present study we examined whether periodic K+ channel activity may cause changes of cell volume, and whether K+ channel activity is distributed in a uniform way in MDCK-F cells. After determining the average volume of MDCK-F cells (2013+/-270 microm3; n=8) by means of atomic force microscopy we deduced volume changes by calculating the K+ efflux during bursts of K+ channel activity. Therefore, we measured the membrane conductance of MDCK-F cells which periodically rose by 22.3+/-2.5 nS from a resting level of 6.5+/-1.4 nS (n=12), and we measured the membrane potential which hyperpolarized in parallel from -35.4+/-1.2 mV to -71.6+/-1.8 mV (n=11). The distribution of K+ channel activity was assessed by locally superfusing the front or rear end of migrating MDCK-F cells with the K+ channel blocker charybdotoxin (CTX). Only exposure of the rear end to CTX inhibited migration providing evidence for "horizontal" polarization of K+ channel activity in transformed MDCK-F cells. This is in contrast to the "vertical" polarization in parent MDCK cells. We propose that the asymmetrical distribution of K+ channel activity is a prerequisite for migration of MDCK-F cells.
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PMID:Polarized ion transport during migration of transformed Madin-Darby canine kidney cells. 747 36

N-Nitrosobutyl(4-hydroxybutyl)amine (BBN) is a selective bladder carcinogen in rats. Its organ specificity may depend on several factors, including metabolic activation, DNA alkylation and repair within the target organ. Metabolic activation of BBN, which is asymmetrical, may result in butylating and 4-hydroxybutylating species. To test this view, BBN was administered as a single oral dose of 20 or 120 mg/rat or six doses of 20 mg/rat over 2 weeks. The animals given the single 120 mg dose were killed 3, 6 and 24 h after treatment. Rats given 20 mg or 6 x 20 mg BBN were killed 24 h after the last dose. DNA from liver and urothelial cells was hydrolyzed and analyzed for O6-butylguanine (O6-BuG) and O6-(4-hydroxybutyl)guanine [O6-(4-OH-Bu)G] as their pentafluorobenzyl-trimethylsilyl derivatives by high-resolution gas chromatography--negative ion chemical ionization mass spectrometry with selective ion recording after immunoaffinity extraction. Polyclonal antibodies raised against O6-(4-hydroxybutyl)-guanosine [O6-(4-OH-Bu)GR] were coupled to CNBr-activated Sepharose 4B. This was mixed with a gel coupled to antibodies raised against O6-BuG, already available in the laboratory, and the mixed gel was used for the one-step sample clean-up, enrichment and extraction of O6-(4-OH-Bu)G and O6-BuG from hydrolyzed DNA. O6-BuG in urothelial DNA of rats given a single dose of 120 mg BBN increased from 0.44 +/- 0.12 mumol/mol guanine (mean +/- SE) 3 h after treatment, to 17.9 +/- 7.23 mumol/mol guanine at 24 h. O6-(4-OH-Bu)G in the same tissue was 7.7 +/- 3.19 mumol/mol guanine 3 h after treatment and 12.2 +/- 7.01 mumol/mol guanine at 24 h. O6-BuG and O6-(4-OH-Bu)G were always lower in the liver than in urothelial cells. Twenty-four hours after a single dose of 20 mg BBN, urothelial O6-BuG was 5.41 +/- 1.73 mumol/mol guanine and did not accumulate after six doses of 20 mg/rat BBN, since it was 2.59 +/- 1.23 mumol/mol guanine 24 h after the last dose. O6-BuG in liver DNA was detectable after the single dose of 20 mg, but not after 6 x 20 mg/rat BBN. O6-(4-OH-Bu)G was not detected in either the bladder or the liver after 20 mg or after the six doses of BBN.(ABSTRACT TRUNCATED AT 400 WORDS)
Carcinogenesis 1994 Oct
PMID:Detection of O6-butyl- and O6-(4-hydroxybutyl)guanine in urothelial and hepatic DNA of rats given the bladder carcinogen N-nitrosobutyl(4-hydroxybutyl)amine. 795 70

The metabolic dealkylation of nine nitrosodialkylamines, including five symmetrical (nitrosodimethylamine, nitrosodiethylamine, nitrosodipropylamine, nitrosodibutylamine and nitrosodiamylamine) and four asymmetrical nitrosodialkylamines (nitrosomethylethylamine, nitrosomethylpropylamine, nitrosomethylbutylamine and nitrosomethylamylamine), was investigated in 14 samples of human liver microsomes. All these nitrosodialkylamines were dealkytated to aldehydes that were separated by reversed phase HPLC and UV detected as dinitrophenylhydrazones. As the length of the alkyl chain increased from methyl to pentyl, dealkylation of symmetrical nitrosodialkylamines became less efficiently catalyzed by cytochrome P450. Conversely, oxidation of the methyl moiety of asymmetrical nitrosomethylalkylamines increased with the size of the alkyl moiety, while dealkylation of the longer alkyl group decreased. N-Dealkylase activities were significantly correlated with P450 activities measured in human liver microsomes. These catalytic activities involve CYP2A6 (coumarin 7-hydroxylation), CYP2C (mephenytoin 4-hydroxylation and tolbutamide hydroxylation), CYP2D6 (dextromethorphan O-demethylation), CYP2E1 (chlorzoxazone and p-nitrophenol hydroxylation) and CYP3A4 (nifedipine oxidation). By using 10 heterologously expressed P450s, it was shown that nitrosodimethylamine was mainly demethylated by CYP2E1. However, such enzyme specificity was lost with increasing size of the alkyl group. Therefore, the chain length of the alkyl group of nitrosodialkylamines determined the P450 involved in its oxidation. All these results emphasize that the catalytic site of P450 2EI has a geometric configuration such that only small molecules like nitrosodimethylamine fit favorably within the putative active site of the enzyme. Furthermore, there is good evidence that P450s other than P450 2E1, such as P450 2A6, 2C8/2C9/2C19 and 3A4, are involved in the metabolism of nitrosodialkylamines bearing bulky alkyl chains.
Carcinogenesis 1996 Sep
PMID:Cytochrome P450 metabolic dealkylation of nine N-nitrosodialkylamines by human liver microsomes. 882 31

Two distinct bidirectional selective breedings for quantitative traits were initiated from identical genetically heterogeneous mouse populations. The resulting lines are characterized by maximal or minimal acute inflammatory responsiveness (AIR): AIRmax and AIRmin lines, respectively, and by resistance or susceptibility to chemical skin tumorigenesis: Car-R and Car-S lines, respectively. The AIR response to s.c. injection of polyacrylamide microbeads, measured by cell content in the local exudate, was 10 times higher in AIRmax than in AIRmin mice. The response to selection was asymmetrical: the realized heritability was 0.26 in AIRmax and 0.008 in AIRmin, and resulted from the additive effect of 7-11 quantitative trait loci (QTL). Low responsiveness was globally dominant in F1 and 48% of F2 segregant variance was found to be due to genetic factors. These findings are the first demonstration of innate regulation of AIR by germ line genes. Susceptibility to skin tumorigenesis induced by a two-stage initiation (DMBA)-promotion (TPA) protocol was lower in AIRmax mice than in AIRmin mice, a 6-fold difference in tumor induction rate. Intense AIR was found to be associated with resistance, and low AIR with susceptibility to tumorigenesis, in F2 segregants chosen for extreme AIR phenotypes. At least some of the AIR QTLs therefore contain genes controlling tumorigenesis. Tumor phenotypes differed more in Car-R and Car-S than in AIRmax and AIRmin lines, indicating that QTLs unrelated to AIR, contribute to the host response to tumorigenesis. The extreme phenotypes/genotypes of the four selected lines and the known genetic constitution of their foundation population, offer new possibilities to discriminate the genes/mechanisms controlling two important traits: AIR and response to chemical tumorigenesis. Collaborative projects will be favorably considered. The description of tumor resistance genes in AIRmax and Car-R mice may be helpful for epidemiology and therapy of human cancer.
Carcinogenesis 1998 Feb
PMID:Effect of genetic modification of acute inflammatory responsiveness on tumorigenesis in the mouse. 949 86

Gastrin is a hormone regulating gastric acid secretion and the growth of the gastrointestinal epithelium. It is expressed by endocrine tumors and by adenocarcinomas of the gastroenteropancreatic region and may represent an autocrine tumor growth factor. Gastrin is also implicated in the genesis of peptic ulcer disease both in conjunction with H. pylori infections and with gastrin-producing tumors. The secretion and expression of gastrin are under the paracrine control of somatostatin, produced by D cells situated in close contact with gastrin-producing G cells. D cells also contain neuronal nitric oxide synthase and appear to regulate apoptosis of G cells by paracrine release of nitric oxide. Both G and D cells are derived from a common multihormonal precursor cell present in the regenerative (isthmus) region of the gastric units. The precursor cells have been suggested to undergo asymmetrical divisions resulting in gastrin- and somatostatin-producing daughter cells that remain in paracrine contact during their migration into the glands. The precursor cells also give rise to the third main antropyloric endocrine cell type; the serotonin-producing EC cell. The maturation of all of these cell types is regulated by a number of transcription factors containing homeobox motifs (Pdx-1, Pax 4 and 6, Isl-1, Nkx6.1). Many of these also regulate the development of the central nervous system and the pancreas. The use of different combinations of these factors for regulating the expression of different hormones may explain the phenomenon of abberant hormone expression during development and carcinogenesis and the occurrence of multihormonal cells.
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PMID:Developmental biology of gastrin and somatostatin cells in the antropyloric mucosa of the stomach. 1070 44

Male Wistar rats received a single i.v. injection of the oesophageal carcinogen N-nitroso[methyl-14C]-methylbenzylnitrosamine (2.5 mg/kg body weight). Rapid distribution of the carcinogen occurred, with highest initial concentrations in liver and kidney. Within 10 min after the injection, 14C-labelled metabolites accounted for 50% of the total radioactivity present in the oesophagus, for approximately 25% in liver and forestomach, and for less than 20% in all other organs investigated. Decay of the carcinogen in rat serum followed first-order kinetics with a half-life of 35 min. Of the total radioactivity administered, 49% was exhaled as 14CO2 within 10 h and an additional 5-10% was excreted via urine and faeces. Four hours after a single i.v. injection of N-nitroso-[methyl-14C]benzylnitrosamine methylation of purine bases in DNA was most extensive in the oesophagus, followed by liver, lung and forestomach DNA. In the remaining tissues, DNA methylation was either considerably less (kidney, glandular stomach, spleen) or not at all detectable (ileum, colon, brain). At this time the concentration of the promutagenic base O6-methylguanine in oesophageal DNA was six times higher than in lung and nine times higher than in hepatic DNA. These data suggest that in the rat the selective induction of oesophageal tumours by N-nitrosomethylbenzylamine and related asymmetrical nitrosamines is mediated by a preferential bioactivation of the carcinogen in the target organ.
Carcinogenesis 1980
PMID:Preferential methylation of target organ DNA by the oesophageal carcinogen N-nitrosomethylbenzylamine. 1121 58

Estrogen-induced signaling mediated by estrogen receptors (ERs) is also affected by aberrant ERs that act as constitutively active or dominant negative modulators. Variant ERs can contribute to carcinogenesis and to the loss of estrogen responsiveness, rendering antiestrogen therapy ineffective. Determining target gene response during co-synthesis of different ER species is difficult, because dimers formed in the presence of more than one ER species are a heterogenous population of homo- or heterodimers. We engineered a homofusion ERalpha as a prototype single-chain receptor by genetically conjugating two ER monomers into a covalently fused single-chain protein to obtain a homogeneous population. This permits analysis of symmetrical or asymmetrical mutations that simulate variant homo- and heterodimers. Although a monomer, the homofusion receptor exhibited similar biochemical and functional properties to the dimeric ERalpha. We used activation function-2 (AF2) defective mutants as a model in either one or both receptor domains for a dominant-negative phenotype by suppressing the reporter activity induced by the WT receptor. When co-expressed with ERalpha, the fusion variant deficient in both AF2 functions suppressed the reporter activity effectively induced by ERalpha. These results show the utility of fusion receptors as models for generation of receptor-based agonists and antagonists.
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PMID:Fusion estrogen receptor proteins: toward the development of receptor-based agonists and antagonists. 1151 59

WNT/planar cell polarity (PCP) signaling pathway controls tissue polarity and cell movement through the activation of RHOA, c-Jun N-terminal kinase (JNK), and nemo-like kinase (NLK) signaling cascades. PCP is induced in Drosophila by the asymmetrical localization of Frizzled-Dishevelled-Diego-Starry night (Flamingo) complex and Van Gogh (Strabismus)-Prickle complex. Here, WNT/PCP signaling pathway implicated in human carcinogenesis is reviewed. Human WNT5A, WNT5B, and WNT11 are representative non-canonical WNTs transducing PCP signals through FZD3 or FZD6 receptors, and ROR1, ROR2 or PTK7 co-receptors. Human VANGL1, VANGL2 (Van Gogh homologs), CELSR1, CELSR2, CELSR3 (Starry night homologs), DVL1, DVL2, DVL3 (Dishevelled homologs), PRICKLE1, PRICKLE2 (Prickle homologs), and ANKRD6 (Diego homolog) are core PCP signaling molecules. MAGI3 assembles FZD, VANGL, PTEN, and adhesion molecules. Dishevelled-dependent WNT/PCP signals are transduced to the RHOA signaling cascade through Formin homology proteins DAAM1 and DAAM2, and to the JNK signaling cascade through MAPKKKs and MAPKK4/7. Dishevelled-independent WNT/ PCP signals are transduced to the NLK signaling cascade through MAP3K7 (TAK1). ANKRD6, NKD1 and NKD2 induce class switch from the WNT/GSK3beta signaling pathway to the WNT/PCP signaling pathway. WNT5A is up-regulated in various types of human cancer, such as gastric cancer, lung cancer, and melanoma. FZD3/FZD6 receptor and ROR2 co-receptor transduce WNT5A signal in gastric cancer. Aberrant activation of WNT/PCP signaling pathway in human cancer leads to more malignant phenotypes, such as abnormal tissue polarity, invasion, and metastasis. cDNA-PCR, microarray or ELISA reflecting aberrant activation of WNT/PCP signaling pathway could be developed as novel cancer prognostics. Single nucleotide polymorphism (SNP) and copy number polymorphism (CNP) of WNT/PCP signaling molecules mentioned above are suitable for use in screening of cancer predisposition, especially for gastric cancer. Antibody, RNAi, or small molecule compounds to regulate the function of WNT/PCP signaling molecules mentioned above are good candidates for development as novel cancer therapeutics.
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PMID:WNT/PCP signaling pathway and human cancer (review). 1627 60

Large cell nuclei with at least eight distinct morphologies have been discovered throughout the fetal gut (5-7 weeks), colonic adenomas, and adenocarcinomas, five of which are not present in the normal adult colon. The most remarkable nuclear forms are hollow bells, approximately 10-15 microns in height and about 7-10 microns in bell mouth diameter. When encased in tubular syncytia, these bell-shaped structures divide symmetrically by an amitotic nuclear fission process resembling the separation of two paper cups. Seven other nuclear morphotypes emerge from the bell-shaped nuclei within the syncytia by asymmetrical amitotic nuclear fission. Cells containing these differentiated nuclear forms subsequently divide extra-syncytially by mitoses that form clonal populations of cells with identical nuclear morphotypes in embryos, adenomas, adenocarcinomas, and metastases. Cells with bell-shaped nuclei thus appear to be responsible for both net growth and differentiation in the embryonic gut, adenomas, and adenocarcinomas, and fulfill the requirements for post-embryonic stem cells in colon organogenesis and carcinogenesis.
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PMID:Bell-shaped nuclei dividing by symmetrical and asymmetrical nuclear fission have qualities of stem cells in human colonic embryogenesis and carcinogenesis. 1636 58


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