Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43146 (tumour suppressor)
 5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mutagenic 'fingerprint' of the cooked food carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) was determined in a Chinese hamster cell line genetically engineered to express human CYP1A2 (XEMh1A2-MZ). The parental Chinese hamster V79 and XEMh1A2-MZ cells were exposed to PhIP at various concentrations for 24h. There was a dose-dependent increase in frequency of mutations at the hypoxanthine-guanine phosphoribosyltransferase (hprt) locus only in the metabolically competent XEMh1A2-MZ cells. The mutant frequency ranged from 25 to 90 X 10(-6) with final concentrations of 2.5 to 100 microM PhIP compared to 8 X 10(-6) in the solvent controls and the V79MZ cells. The molecular nature of the PhIP-induced mutations in XEMh1A2-MZ cells was determined by examining DNA sequence modifications at the hprt locus in forty five 6-thioguanine resistant (6-TGr) mutant clones. Single base substitutions predominantly GC-->TA transversions, were the major class of PhIP-induced mutation. However, a -1 frameshift 'hotspot' in a 5'-GGGA sequence was also observed. With the exception of a compound modification, all of the PhIP-induced mutations involved G.C base pairs. This is consistent with the previously observed PhIP-induced mutations in cultured mammalian cells and 32P-postlabelling experiments that show PhIP adducts to the guanine base and that major adduct is at the C8 position. Furthermore, nearly all of these mutations involved guanine bases on the non-transcribed strand which is possibly indicative of preferential repair of PhIP adducts from the transcribed strand. Nearest neighbor analysis of induced base substitutions indicates a preference for 5' guanine and 3' adenine. These data effectively define a mutation 'fingerprint' for PhIP, which may provide the basis for definitive studies on the role of PhIP in diet associated cancers such as tumours of colon. It is, therefore, intriguing that in their recent report of mutation in tumours of the colon induced by PhIP in male rate Kakiuchi et al. (Proc. Natl Acad. Sci. USA, 92, 910-914) report that four out of eight tumors had identical mutation of the tumour suppressor gene apc which is comprised of a -1 G frameshift in a 5'-GGGA sequence.
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PMID:Mutational spectra of the dietary carcinogen 2-amino-1-methyl-6- phenylimidazo[4,5-b]pyridine(PhIP) at the Chinese hamsters hprt locus. 862 68

This paper quantifies the resilience of a gene to each class of base substitution. The resilience of a gene is defined as the set of probabilities of synonymous base substitution (one for each type of base substitution on each DNA strand), and is derived from the fraction of all possible substitutions which result in no change of encoded amino acids. We discuss the resilience of the common mutational target genes, lacI and hypoxanthine-guanine phosphoribosyltransferase (hprt), and the p53 tumour suppressor gene. There are inherent strand biases to mutation in terms of the resilience differences between the non-template and template DNA strands. The ability to quantify resilience differences between the two DNA strands contributes to our understanding of strand bias to mutation.
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PMID:DNA strand biases and the mutational resilience of genes. 968 87

Two mammalian cell mutation assays, the HPRT/V79 assay and the TK/mouse lymphoma assay, were compared for their ability to respond to the genotoxic chemicals ethyl methanesulfonate (EMS) and mitomycin C (MMC). Whereas EMS induced a high mutant frequency at both loci, MMC produced few mutants at the hprt locus, but induced a large number of mutants at the tk locus. Southern blotting analysis showed that this difference was due to the type of genetic damage induced by the two chemicals. Intragenic changes ranging from point mutations to loss of the entire gene were recovered as viable mutants at both the hprt and tk loci. Thus, EMS which causes mainly intragenic mutations induced similar mutant frequencies at both loci. The large multilocus deletions induced by MMC, in which the damage was assumed in many cases to extend into a gene essential for growth since most TK mutants were slow-growing, could not be recovered at the hprt locus. Whereas both loci will detect intergenic mutations, mutants carrying large-scale damage are recoverable only at the heterozygous tk locus. At the hemizygous hprt locus no homologous chromosome exists to provide the function of essential genes if these are lost along with hprt in multilocus deletions. Most human cancers develop as a highly complex process involving both gene and multilocus mutations in oncogenes and tumour suppressor genes. Thus the TK/mouse lymphoma assay is a more appropriate in vitro test for the detection of chemicals capable of causing the types of DNA lesions important in human cancer.
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PMID:Molecular analysis of chemically-induced mutations in mammalian cell assays. 2065 Jan 22