INDUCTION OF MUTATIONS IN POLIOMYELITIS VIRUS BY DIRECT ACTION OF PROFLAVINE ON VIRUS RNA.
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Acridines↗
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Induction of mutations in V79-4 mammalian cells under hypoxic and aerobic conditions by the cytotoxic 2-nitroimidazole-aziridines, RSU-1069 and RSU-1131. The influence of cellular glutathione.
Incubation of the 2-nitroimidazole-aziridine, RSU-1069 [1-(2-nitro-1-imidazolyl)-3-(1-aziridinyl)-2-propanol], and its monomethylaziridine analogue, RSU-1131 [1-(2-nitro-1-imidazolyl)-3-(1-(2-methylaziridinyl))-2-propanol], with V79-4 mammalian cells for 2 hr under aerobic or hypoxic conditions induces mutations as measured at the hypoxanthine phosphoribosyl transferase locus. The ability of these agents to induce mutations is increased by a factor of 12-14 under hypoxic conditions. The increased cytotoxicity of these agents under hypoxic conditions was confirmed following a 2 hr incubation period. Decreasing the glutathione (GSH) content of the cells with buthionine-(S,R)-sulphoximine to < 1% of the control generally results in an increase in the cytotoxicity and mutagenicity of these agents under both aerobic and hypoxic conditions. Since these agents do not modify the cellular GSH levels, it is inferred that the thiols partially detoxify through removal of a reactive metabolite of the agents, under hypoxic conditions, or removal of known DNA adducts, and not through their interaction with the agents themselves. Under aerobic conditions, the formation of mutations is consistent with the established monofunctional action of these agents whereas under hypoxic conditions the bifunctional action predominates for mutation induction, based upon the large differential aerobic:hypoxic effect. From a comparison of the number of mutations per lethal event, the effect of thiol depletion is more pronounced for cytotoxicity than for mutation induction by these agents. In summary, these agents are considered to be weak mutagens towards V79-4 cells under aerobic conditions when compared with other DNA alkylating agents, although they are more potent under anoxic conditions.
Animals↗
[Biochemical mutations in Torulopsis utilis following the action of ionizing irradiations].
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Candida↗
An overexpressed N-ras proto-oncogene cooperates with N-methylnitrosourea in mouse mammary carcinogenesis.
The induction of tumors with chemicals and the production of transgenic animals are two experimental approaches to study oncogene involvement in carcinogenesis. The combination of both strategies offers an excellent model system to study tumor development. This study analyzes the potential cooperation of N-methylnitrosourea (MNU) treatment and N-ras proto-oncogene overexpression in tumorigenesis in transgenic mice. The overexpression of the N-ras proto-oncogene in these animals is associated with development of mammary tumors and lymphomas. After MNU treatment we analyzed tumor incidence and latency, levels of transgene expression, and pattern of ras mutations in codons 12, 13, and 61 of H-, K-, and N-ras genes in both tumor types. Transgenic mice treated with MNU had significantly (P < 0.001) shorter latency of appearance of mammary tumors [8.6 +/- 3.0 (SD) months] than phosphate-buffered saline-treated transgenics (12.8 +/- 2.3 months). All mammary tumors overexpressed the N-ras transgene and lacked ras mutations. Moreover, MNU-treated transgenics had an incidence and latency of lymphomas similar to that of MNU-treated nontransgenic mice. No significant differences in incidence of point mutations (K-ras codon 12 or 13 and N-ras codon 61) in lymphomas were seen between these two groups. All lymphomas overexpressed the N-ras transgene, except for those carrying a K-ras point mutation. Overexpression of the N-ras proto-oncogene cooperates with non-ras genes mutated by MNU in mouse mammary carcinogenesis. Conversely, N-ras proto-oncogene overexpression does not show cooperation with MNU in lymphomagenesis in our system. This study suggests that proto-oncogene overexpression may be a mechanism of activation of the ras pathway, alternative to point mutation. Similarly to actions for ras genes activated by point mutation, overexpression of the N-ras protooncogene predisposes to tumorigenesis and cooperates with a carcinogen in tumorigenesis. The possibility that ras overexpression plays a role in human breast tumorigenesis requires active investigation.
Animals↗
Action of clinically utilized 5-nitroimidazoles on microorganisms.
Various nitroimidazoles are used as antimicrobial and radiosensitizing agents in human medicine. Of these, 5-nitroimidazoles show high selective toxicity for anaerobic prokaryotes and eukaryotes. This review discusses the effects of 5-nitroimidazoles on microorganisms, i.e. microbicidal action, radiosensitizing action, inhibition of photosynthetic microorganisms, and induction of mutations. All these actions are enhanced by anaerobiosis and inhibited by aerobiosis or by the presence of certain reducible compounds. There is no indication that antimicrobial action could be dissociated from mutagenic properties. Relative resistance to 5-nitroimidazoles has been detected in some isolates of Bacteroides fragilis and Trichomonas vaginalis and was experimentally developed in B. fragilis and various trichomonads. Nitroimidazoles enter the microorganisms by diffusion. Facilitated transport has not been detected. The compound is reduced by low oxidation-reduction potential ferredoxin and similar electron transport components in the cell. In microorganisms highly susceptible to metronidazole, such compounds play a significant metabolic role. The reduction increases the outside-inside concentration gradient and thus drives further uptake. Certain short-lived products of the reduction are responsible for the cytotoxic action. In less susceptible organisms only limited amounts of such products are formed, and thus the cells are not killed but may undergo mutations. A major component of cytotoxicity is damage to DNA but other mechanisms cannot be excluded at present.
Anaerobiosis↗
Electrostatic control of GTP and GDP binding in the oncoprotein p21ras.
BACKGROUND: p21ras is one of the GTP-binding proteins that act as intercellular molecular switches. The GTP-bound form of p21ras sends a growth-promoting signal that is terminated once the protein is cycled back into its GDP-bound form. The interaction of guanine-nucleotide-exchange factors (GEFs) with p21ras leads to activation of the protein by promoting GDP --> GTP exchange. Oncogenic mutations of p21ras trap the protein in its biological active GTP-bound form. Other mutations interfere with the activity of GEF. Thus, it is important to explore the structural basis for the action of different mutations. RESULTS: The crystal structures of p21ras are correlated with the binding affinities of GTP and GDP by calculating the relevant electrostatic energies. It is demonstrated that such calculations can provide a road map to the location of 'hot' residues whose mutations are likely to change functional properties of the protein. Furthermore, calculations of the effect of specific mutations on GTP and GDP binding are consistent with those observed. This helps to analyze and locate functionally important parts of the protein. CONCLUSIONS: Our calculations indicate that the protein main chain provides a major contribution to the binding energies of nucleotides and probably plays a key role in relaying the effect of GEF action. Analysis of p21ras mutations in residues that are important for the proper function of GEFs suggests that the region comprising residues 62-67 in p21ras is the major GEF-binding site. This analysis and our computer simulations indicate that the effect of GEF is probably propagated to the P-loop (residues 10-17) through interaction between Gly60 and Gly12. This then reduces the interaction between the main-chain dipoles of the P-loop and the nucleotide. Finally, the results also suggest a possible relationship between the GTP --> GDP structural transition and the catalytic effect of the GTPase-activating protein.
Binding Sites↗
Gene mutation in patients with primary open-angle glaucoma in a pedigree in China.
OBJECTIVE: To investigate the genetic basis of the pathogenesis of a Guangzhou (GZ.1) pedigree with primary open-angle glaucoma (POAG). METHODS: DNA fragments of the trabecular meshwork inducible glucocorticoid response protein (TIGR) gene from 4 typical POAG patients and 2 normal subjects were amplified by polymerase chain reaction (PCR). The amplified PCR fragment was cloned into a pT-Adv vector, and direct sequencing was carried out on an ABI-373 automated DNA sequencer using dyeterminator chemistry to detect the mutation. RESULTS: The TIGR gene mutation was identified in the selected subjects of this pedigree. This mutation is a "C-to-T" transition at position 370, different from that of western countries and equivalent to the position change found in Japanese patients with familial POAG. No mutation was found in the TIGR gene fragment in 2 normal subjects of the pedigree. CONCLUSIONS: These preliminary results provide insights into the pathogenesis of POAG by the TIGR gene mutation, and into the underlying action of the different mutations in oriental and western peoples.
Cytoskeletal Proteins↗
The Tyr-265-to-Cys mutator mutant of DNA polymerase beta induces a mutator phenotype in mouse LN12 cells.
DNA polymerase beta functions in both base excision repair and meiosis. Errors committed by polymerase beta during these processes could result in mutations. Using a complementation system, in which rat DNA polymerase beta substitutes for DNA polymerase I of Escherichia coli, we previously isolated a DNA polymerase beta mutant in which Tyr-265 was altered to Cys (Y265C). The Y265C mutant is dominant to wild-type DNA polymerase beta and possesses an intrinsic mutator activity. We now have expressed the wild-type DNA polymerase and the Y265C mutator mutant in mouse LN12 cells, which have endogenous DNA polymerase beta activity. We demonstrate that expression of the Y265C mutator mutant in the LN12 cells results in an 8-fold increase in the spontaneous mutation frequency of lambdacII mutants compared with expression of the wild-type protein. Expression of Y265C results in at least a 40-fold increase in the frequency of deletions of three bases or more and a 7-fold increase in point mutations. Our results suggest that the mutations we observe in vivo result directly from the action of the mutator polymerase. To our knowledge, this is the first demonstration of a mutator phenotype resulting from expression of a DNA polymerase mutator mutant in mammalian cells. This work raises the possibility that variant polymerases may act in a dominant fashion in human cells, leading to genetic instability and carcinogenesis.
Amino Acid Substitution↗
Comparison of actionable alterations in cancers with kinase fusion, mutation, and copy number alteration.
Kinase-related gene fusion and point mutations play pivotal roles as drivers in cancer, necessitating optimized, targeted therapy against these alterations. The efficacy of molecularly targeted therapeutics varies depending on the specific alteration, with great success reported for such therapeutics in the treatment of cancer with kinase fusion proteins. However, the involvement of actionable alterations in solid tumors, especially regarding kinase fusions, remains unclear. Therefore, in this study, we aimed to compare the number of actionable alterations in patients with tyrosine or serine/threonine kinase domain fusions, mutations, and copy number alterations (CNAs). We analyzed 613 patients with 40 solid cancer types who visited our division between June 2020 and April 2024. Furthermore, to detect alterations involving multiple-fusion calling, we performed comprehensive genomic sequencing using FoundationOne® companion diagnostic (F1CDx) and FoundationOne® Liquid companion diagnostic (F1LCDx). Patient characteristics and genomic profiles were analyzed to assess the frequency and distribution of actionable alterations across different cancer types. Notably, 44 of the 613 patients had fusions involving kinases, transcriptional regulators, or tumor suppressors. F1CDx and F1LCDx detected 13 cases with kinase-domain fusions. We identified 117 patients with kinase-domain mutations and 58 with kinase-domain CNAs. The number of actionable alterations in patients with kinase-domain fusion, mutation, or CNA (median [interquartile range; IQR]) was 2 (1-3), 5 (3-7), and 6 (4-8), respectively. Patients with kinase fusion had significantly fewer actionable alterations than those with kinase-domain mutations and CNAs. However, those with fusion involving tumor suppressors tended to have more actionable alterations (median [IQR]; 4 [2-9]). Cancers with kinase fusions exhibited fewer actionable alterations than those with kinase mutations and CNAs. These findings underscore the importance of detecting kinase alterations and indicate the pivotal role of kinase fusions as strong drivers of cancer development, highlighting their potential as prime targets for molecular therapeutics.
Humans↗
Replacement of posterior by anterior structures in the Drosophila wing caused by the mutation apterous-blot.
The recessive mutation apterous-blot in Drosophila melanogaster causes replacement of posterior wing structures by anterior ones, with variable penetrance and expressivity. Extreme transformations resemble mirror-image duplicate anterior wings as in the mutant engrailed. Anterior structures in the posterior wing only appear on the dorsal surface. Duplications solely of posterior structures are also seen. Clonal analysis shows that extra cell proliferation occurs in the posterior area but is complete by 108 h after egg deposition. Lineage analysis is consistent with a clonal perpetuation of the transformation. Genetic mosaics to test the cell-autonomy of apterous-blot show that it is not autonomously expressed in clones. The results of lineage analysis, the phenotypes of combinations of apterous-blot with other apterous alleles including a deletion for the locus and with various other homoeotic mutations, are together used to distinguish three alternative modes of action of this mutation. It is concluded that apterous-blot is unlikely to be a selector gene mutation but instead may cause the transformation by an event like transdetermination following a local failure in cell function in the wing disc.
Animals↗
Modeling of IK1 mutations in human left ventricular myocytes and tissue.
Elucidation of the cellular basis of arrhythmias in ion channelopathy disorders is complicated by the inherent difficulties in studying human cardiac tissue. Thus we used a computer modeling approach to study the mechanisms of cellular dysfunction induced by mutations in inward rectifier potassium channel (K(ir))2.1 that cause Andersen-Tawil syndrome (ATS). ATS is an autosomal dominant disorder associated with ventricular arrhythmias that uncommonly degenerate into the lethal arrhythmia torsade de pointes. We simulated the cellular and tissue effects of a potent disease-causing mutation D71V K(ir)2.1 with mathematical models of human ventricular myocytes and a bidomain model of transmural conduction. The D71V K(ir)2.1 mutation caused significant action potential duration prolongation in subendocardial, midmyocardial, and subepicardial myocytes but did not significantly increase transmural dispersion of repolarization. Simulations of the D71V mutation at shorter cycle lengths induced stable action potential alternans in midmyocardial, but not subendocardial or subepicardial cells. The action potential alternans was manifested as an abbreviated QRS complex in the transmural ECG, the result of action potential propagation failure in the midmyocardial tissue. In addition, our simulations of D71V mutation recapitulate several key ECG features of ATS, including QT prolongation, T-wave flattening, and QRS widening. Thus our modeling approach faithfully recapitulates several features of ATS and provides a mechanistic explanation for the low frequency of torsade de pointes arrhythmia in ATS.
Action Potentials↗
Mode of action considerations in the use of transgenic animals for mutagenicity and carcinogenicity evaluations.
Genetically altered rodent models can be useful in facilitating the extrapolation of results from animal carcinogenicity studies to human risk assessment by contributing mode of action data. Transgenic mutation models make it possible to analyze mutations in vivo in any tissue of interest. Validation studies using genotoxic and epigenetic carcinogens indicated a good correlation between mutation induction and the tumor target tissues and have provided data on mode of tumorigenic action. However, carcinogenesis is a complex process and mutation induction in a given tissue does not always lead to tumors in that tissue. Genetically altered animal models such as the p53 +/- mouse can be useful in differentiating genotoxic carcinogens from those operating by non-genotoxic mechanisms. An understanding of the tumor responses of these short-term alternative transgenic and knockout mice to epigenetic events such as tissue injury and enzyme induction at high maximum tolerated doses will eventually increase our level of confidence in these animal models for hazard evaluation and mechanistic studies.
Animals↗
[Induction of mutations in mammalian cells by the action of live vaccinal strains of poliomyelitis virus].
The attenuated strains' poliomyelitis virus induces mutagenesis in human and Chinese hamster cultured cells. The mutagenic action of the poliovirus is detected at chromosome and gene levels and directly depends on the multiplicity of cell infection. Possibilities for developing nonmutagenic antivirus vaccines are discussed.
Animals↗
FGF23, PHEX, and MEPE regulation of phosphate homeostasis and skeletal mineralization.
There is evidence for a hormone/enzyme/extracellular matrix protein cascade involving fibroblastic growth factor 23 (FGF23), a phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX), and a matrix extracellular phosphoglycoprotein (MEPE) that regulates systemic phosphate homeostasis and mineralization. Genetic studies of autosomal dominant hypophosphatemic rickets (ADHR) and X-linked hypophosphatemia (XLH) identified the phosphaturic hormone FGF23 and the membrane metalloprotease PHEX, and investigations of tumor-induced osteomalacia (TIO) discovered the extracellular matrix protein MEPE. Similarities between ADHR, XLH, and TIO suggest a model to explain the common pathogenesis of renal phosphate wasting and defective mineralization in these disorders. In this model, increments in FGF23 and MEPE, respectively, cause renal phosphate wasting and intrinsic mineralization abnormalities. FGF23 elevations in ADHR are due to mutations of FGF23 that block its degradation, in XLH from indirect actions of inactivating mutations of PHEX to modify the expression and/or degradation of FGF23 and MEPE, and in TIO because of increased production of FGF23 and MEPE. Although this model is attractive, several aspects need to be validated. First, the enzymes responsible for metabolizing FGF23 and MEPE need to be established. Second, the physiologically relevant PHEX substrates and the mechanisms whereby PHEX controls FGF23 and MEPE metabolism need to be elucidated. Finally, additional studies are required to establish the molecular mechanisms of FGF23 and MEPE actions on kidney and bone, as well as to confirm the role of these and other potential "phosphatonins," such as frizzled related protein-4, in the pathogenesis of the renal and skeletal phenotypes in XLH and TIO. Unraveling the components of this hormone/enzyme/extracellular matrix pathway will not only lead to a better understanding of phosphate homeostasis and mineralization but may also improve the diagnosis and treatment of hypo- and hyperphosphatemic disorders.
Animals↗
Isolation of temperature-sensitive mutations of the tyrosine kinase receptor sevenless (sev) in Drosophila and their use in determining its time of action.
Loss-of-function mutations in the sevenless (sev) gene in Drosophila result in the failure to differentiate a specific photoreceptor cell type--namely, the R7 cell. The sev gene encodes a cell-surface receptor tyrosine kinase that functions in the presumptive R7 cell to transduce developmental cues from its neighbors, instructing it to differentiate along the R7 cell pathway. We have isolated temperature-sensitive alleles of sev and used them to show that Sev activity is required for several hours during the development of each R7 cell to specify R7 cell differentiation. Our data also suggest that the presumptive R7 cell remains for approximately 5 hr in an undetermined state in the absence of the Sev-mediated signal before committing to an alternative fate. We have determined the molecular lesions in four of the temperature-sensitive alleles. One of these mutations disrupts the Gly-Xaa-Gly-Xaa-Xaa-Gly consensus in the ATP-binding site of the kinase domain.
Alleles↗
The ELONGATED gene of Arabidopsis acts independently of light and gibberellins in the control of elongation growth.
A novel elongated mutant has been isolated from EMS-mutagenized populations of the Arabidopsis thaliana ga4 mutant. After backcrossing with the Landsberg erecta (Ler) wild-type (WT) followed by selfing, the mutant phenotype was identified in the GA4 background. Seedlings of the mutant, which has been named elg (elongated), are characterized by elongated hypocotyls and petioles, leaves that are narrow and somewhat epinastic and early flowering. Allelism tests with the hy1-hy5 mutants indicate that elg is not allelic with any of these long-hypocotyl mutants. From linkage analyses, the location of elg on chromosome 4, between cer2 and ap2 has been established. The pleiotropic phenotype of elg seedlings is suggestive of a disruption of phytochrome and/or gibberellin (GA) function. Although the elg mutant displays a light-dependent long-hypocotyl phenotype, elg seedlings retain a full range of photomorphogenic responses and the elg mutation acts additively with the photomorphogenic mutants phyB, hy1 and hy2. This suggests that ELG acts independently of phytochrome action. The elg mutation partially suppresses the effect of GA-deficiency on elongation growth, and, although elg ga1 seedlings are more elongated than ga1 seedlings, both genotypes respond in the same way to applied GA. That applied GA and the elg mutation interact additively suggests that ELG acts independently of GA action.
Arabidopsis↗
The abi1-1 mutation blocks ABA signaling downstream of cADPR action.
Arabidopsis thaliana abscisic acid insensitive 1-1 (abi1-1) is a dominant mutant that is insensitive to the inhibition of germination and growth by the plant hormone, abscisic acid (ABA). The mutation severely decreases the catalytic activity of the ABI1 type 2C protein phosphatase (PP2C). However, the site of action of the abi1-1/ABI1 in the ABA signal transduction pathway has not yet been determined. Using single cell assays, we showed that microinjecting mutant abi1-1 protein inhibited the activation of RD29A-GUS and KIN2-GUS in response to ABA, cyclic ADP-ribose (cADPR), and Ca2+. The inhibitory effect of the mutant protein, however, was reversed by co-microinjection of an excess amount of the ABI1 protein. In transgenic Arabidopsis plants, overexpression of abi1-1 rendered the plants insensitive to ABA during germination, whereas overexpression of ABI1 did not have any apparent effect. Moreover, transgenic plants overexpressing abi1-1 were blocked in the induction of ABA-responsive genes; however, overexpression of ABI1 did not affect gene expression. Taken together, our results demonstrate that abi1-1 is likely to be a dominant negative mutation and ABI1 likely acts downstream of cADPR in the ABA-signaling pathway. Our results on ABI1 overexpression in Arabidopsis are not compatible with a negative regulatory role of this phosphatase in ABA responses.
Abscisic Acid↗
SNPs, protein structure, and disease.
Inherited disease susceptibility in humans is most commonly associated with single nucleotide polymorphisms (SNPs). The mechanisms by which this occurs are still poorly understood. We have analyzed the effect of a set of disease-causing missense mutations arising from SNPs, and a set of newly determined SNPs from the general population. Results of in vitro mutagenesis studies, together with the protein structural context of each mutation, are used to develop a model for assigning a mechanism of action of each mutation at the protein level. Ninety percent of the known disease-causing missense mutations examined fit this model, with the vast majority affecting protein stability, through a variety of energy related factors. In sharp contrast, over 70% of the population set are found to be neutral. The remaining 30% are potentially involved in polygenic disease.
Allosteric Regulation↗