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At least 883 records · Page 49Linked to original sources
PubMed1993

High prevalence of mutations at codon 249 of the p53 gene in hepatocellular carcinomas from Senegal.

In hepatocellular carcinoma, mutation within the p53 gene occurs mainly at codon 249 and its frequency has been associated with exposure to aflatoxin. As Senegal is a country where liver cancer incidence is one of the highest in the world and where people are highly exposed to aflatoxin, we screened 15 liver cancer samples from this country for mutation at codon 249 of the p53 gene. Non-tumoral DNA from the patients showed a wild type genotype. Mutation at codon 249 of the p53 gene was detected in 10 of the 15 tumour tissues tested (67%). This frequency of mutation in codon 249 of the p53 gene is the highest described. These results confirmed that there is an association between countries of high aflatoxin intake and a high frequency of mutation in codon 249 of p53 gene, and that HBV alone does not contribute to these base changes.

Base Sequence↗
PubMed2000

Polymorphism at codon 72 of p53 is not associated with cervical cancer risk.

P53 allelic polymorphism at codon 72 has been studied as a possible predisposing factor for cervical carcinogenesis with inconsistent results. Storey and colleagues recently published the interesting finding of a 7-fold increased risk for cervical cancer in women homozygous for the arginine allele at codon 72. This stimulated a number of independent investigations, the majority of which found no association of cervical cancer and arginine homozygosity. With the use of a modified Storey method for determining codon 72 allelotypes, DNA was examined from 431 microdissected, formalin-fixed, archival cervical conization specimens ranging from low-grade squamous lesions to invasive cancer. An alternative independent method using restriction fragment length polymorphism analysis was performed on all arginine homozygotes and all indeterminate cases for confirmation and final allelotype assignment. With the use of Storey's method alone, logistic regression suggested an association (odds ratio, 1.42) between arginine homozygosity and invasive disease. However, with the use of the combined method for accurate allelotyping, this trend disappeared (odds ratio, 1.00), the discordance was clearly resolvable as being due to methodologic variables. With the use of two separate methods for codon 72 allelotyping and accounting for a number of the issues raised in previously published reports, there is no increased risk for invasive cervical cancer associated with arginine homozygosity at codon 72 of p53.

Adenocarcinoma↗
PubMed2003

The soybean retroelement SIRE1 uses stop codon suppression to express its envelope-like protein.

The soybean SIRE1 family of Ty1/copia retrotransposons encodes an envelope-like gene (env-like). We analysed the DNA sequences of nine SIRE1 insertions and observed that the gag/pol and env-like genes are in the same reading frame and separated by a single UAG stop codon. The six nucleotides immediately downstream of the stop codon conform to a degenerate nucleotide motif, CARYYA, which is sufficient to facilitate stop codon suppression in tobacco mosaic virus. In vivo stop codon suppression assays indicate that SIRE1 sequences confer leakiness to the UAG stop codon at an efficiency of 5%. These data suggest that SIRE1 retro-elements use translational suppression to express their envelope-like protein; this is in contrast with all characterized retroviruses, which express the envelope protein from a spliced genomic messenger RNA.

Base Sequence↗
PubMed2005

Adaptive basis of codon usage in the haploid moss Physcomitrella patens.

Patterns of codon usage bias were studied in the moss model species Physcomitrella patens. A total of 92 nuclear, protein coding genes were employed, and estimated levels of gene expression were tested for association with two measures of codon usage bias and other variables hypothesized to be associated with gene expression. Codon bias was found to be positively associated both with estimated levels of gene expression and GC content in the coding parts of studied genes. However, GC content in noncoding parts, that is, introns and 5' and 3' untranslated regions (UTRs), was not associated with estimated levels of gene expression. It is argued that codon bias is not shaped by mutational bias, but rather by weak natural selection for translational efficiency in P. patens. The possible role of life history characteristics in shaping patterns of codon usage in this species is discussed.

Bryopsida↗
PubMed2002

Esophageal cancer in Chinese population: no polymorphism in codon 149 of P21(Waf1/Cip1) cyclin dependent kinase gene.

It has recently been suggested that people of the Indian population who carried the codon 149 polymorphism (GAT-->GGT) of P21(Waf1/Cip1) gene were more susceptible to esophageal cancer and oral cancer than the individuals without that polymorphism. Since esophageal cancer is a high incident neoplasm in China, we analysed the same codon of P21(Waf1/Cip1) in the Chinese population. Blood samples from 80 esophageal cancer patients and 80 normal blood donors were collected for DNA extraction. Methods of Polymerase Chain Reaction (PCR) and direct sequencing were used for detection of the polymorphism in codon 149 of P21(Waf1/Cip1). Bioinformatics analysis was also thoroughly performed for this gene. No polymorphism was found in all samples tested. Bioinformatics analysis revealed that the so-called polymorphism of codon 149 reported previously was a wrong one. In conclusion, no polymorphism exists in codon 149 of P21(Waf1/Cip1). It is not appropriate to use it as a susceptible site of the gene in cancer study.

Asian People↗
PubMed2001

Selenocysteine codons decrease polysome association on endogenous selenoprotein mRNAs.

BACKGROUND: Selenocysteine incorporation has been reported to be inefficient in all systems studied, including Escherichia coli, baculovirus-insect cell systems, rabbit reticulocyte in vitro translation systems, transiently transfected mammalian cells, and intact animals. Nonetheless, full-length selenoproteins containing up to 17 selenocysteine residues are produced in animals, indicating that the efficiency observed in manipulated systems might not accurately reflect the true efficiency of this process in nature. RESULTS: To begin to address this apparent discrepancy, we have examined the polysome profiles of endogenously expressed selenoprotein mRNAs in a mammalian cell line, and compared them with nonselenoprotein mRNAs. We report that three selenoprotein mRNAs, type 1 deiodinase, glutathione peroxidase and selenoprotein P, are under-loaded with ribosomes, based on their predicted open reading frame sizes. The average numbers of ribosomes per mRNA correspond to the sizes predicted by termination at the UGA selenocysteine codons. Appropriate loading on the type 1 deiodinase mRNA is seen following substitution of a cysteine codon for the selenocysteine codon, indicating that the UGA codon confers a translational penalty on the mRNA. Surprisingly, ribosomal loading is also increased by the expression of eukaryotic release factors eRF1 and eRF3. CONCLUSIONS: These results suggest that the presence of a selenocysteine codon confers a translational penalty on selenoprotein mRNAs, and that increased levels of release factors may alter the kinetics of termination.

Animals↗
PubMed2002

An improved DNA-based test for detection of the codon 616 mutation in the alpha cyclic GMP phosphodiesterase gene that causes progressive retinal atrophy in the Cardigan Welsh Corgi.

The aim of the study was to develop an improved test to detect the codon 616 gene mutation in the alpha cyclic GMP phosphodiesterase gene that causes progressive retinal atrophy in the Cardigan Welsh Corgi. We studied 10 control dogs of known genotype at codon 616 of the alpha cyclic GMP phosphodiesterase gene and 80 Cardigan Welsh Corgis of unknown genotype. A polymerase chain reaction (PCR) utilizing a mismatched primer was designed so that it introduced a HinfI restriction enzyme digestion site into the PCR product only if the normal gene sequence was present, the restriction site was not introduced if the codon 616 mutation was present. An additional HinfI site present in the amplified section from both normal and mutant alleles acted as a positive control for restriction enzyme digestion. The PCR reliably amplified a portion of the alpha cyclic GMP phosphodiesterase gene spanning the codon 616 mutation site. Restriction enzyme digestion with HinfI and analysis on a suitable agarose gel reliably ascertained the genotype of the control dogs and was used to identify the genotype of a further 80 test dogs. An improved DNA-based test for detection of the codon 616 mutation in the alpha cyclic GMP phosphodiesterase gene that causes progressive retinal atrophy in the Cardigan Welsh Corgi has been designed. This overcomes potential problems that could be associated with allele-specific PCR tests such as that used previously in a diagnostic test for this gene mutation.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1996

[Incidence of point mutations in Ki-ras codon 12 and 13 in squamous epithelial carcinomas of the head-neck region].

BACKGROUND: Point mutations of ras genes are one of the most frequent genetic alterations in human malignancies with up to over 95% in certain tumors. Some studies have presumed a low incidence of point mutations in Ki-ras gene codons 12 and 13 in squamous cell carcinoma of the head and neck (SCCHN). The objective of this study was to gain more information about the significance of point mutations in Ki-ras codons 12 and 13 by investigation of a high number of cases. METHODS: By employing the polymerase chain reaction with specific primers, 63 fresh tumor biopsies were investigated by the nonradioisotopic single-strand conformation polymorphism (SSCP) analysis. To cooperate the efficiency and to characterize the nature of the point mutations, direct fluorescence-labeled DNA sequencing was performed in two cases. RESULTS: Five out of the 63 (7.9%) SCCHN samples exhibited point mutations in codons 12 and 13 by SSCP analysis. In two out of these mutated cases, a G to T transversion in codon 12.2 of the Ki-ras gene was detected. The analysis of the patient's clinical parameters as well as the histopathological grading and tumor staging revealed no correlation with the Ki-ras point mutation. CONCLUSIONS: Ki-ras point mutations in codons 12 and 13 are a rare event in SCCHN. These data give additional evidence that these genetic alterations do not play a major role in the development of malignancies of the upper aerodigestive tract.

Aged↗
PubMed2004

Codon usage between genomes is constrained by genome-wide mutational processes.

Analysis of genome-wide codon bias shows that only two parameters effectively differentiate the genome-wide codon bias of 100 eubacterial and archaeal organisms. The first parameter correlates with genome GC content, and the second parameter correlates with context-dependent nucleotide bias. Both of these parameters may be calculated from intergenic sequences. Therefore, genome-wide codon bias in eubacteria and archaea may be predicted from intergenic sequences that are not translated. When these two parameters are calculated for genes from nonmammalian eukaryotic organisms, genes from the same organism again have similar values, and genome-wide codon bias may also be predicted from intergenic sequences. In mammals, genes from the same organism are similar only in the second parameter, because GC content varies widely among isochores. Our results suggest that, in general, genome-wide codon bias is determined primarily by mutational processes that act throughout the genome, and only secondarily by selective forces acting on translated sequences.

Animals↗
PubMed2004

An expanded genetic code with a functional quadruplet codon.

With few exceptions the genetic codes of all known organisms encode the same 20 amino acids, yet all that is required to add a new building block are a unique tRNA/aminoacyl-tRNA synthetase pair, a source of the amino acid, and a unique codon that specifies the amino acid. For example, the amber nonsense codon, TAG, together with orthogonal Methanococcus jannaschii or Escherichia coli tRNA/synthetase pairs have been used to genetically encode a variety of unnatural amino acids in E. coli and yeast, respectively. However, the availability of noncoding triplet codons ultimately limits the number of amino acids encoded by any organism. Here, we report the design and generation of an orthogonal synthetase/tRNA pair derived from archaeal tRNA(Lys) sequences that efficiently and selectively incorporates an unnatural amino acid into proteins in response to the quadruplet codon, AGGA. Frameshift suppression with L-homoglutamine (hGln) does not significantly affect protein yields or cell growth rates and is mutually orthogonal with amber suppression, permitting the simultaneous incorporation of two unnatural amino acids, hGln and O-methyl-L-tyrosine, at distinct positions within myoglobin. This work suggests that neither the number of available triplet codons nor the translational machinery itself represents a significant barrier to further expansion of the genetic code.

Amino Acids↗
PubMed1981

Reinitiation of translation from the triplet next to the amber termination codon in the absence of ribosome-releasing factor.

Ribosome releasing factor (RR factor) releases ribosomes from mRNA at the termination codon in Escherichia coli. In the absence of this factor, polypeptides with molecular weights very close to the molecular weight of bacteriophage R17 coat protein were synthesized in vitro under the direction of a mutant R17 phage RNA having an amber mutation at codon 7 of the coat cistron. The major coat-protein-like product shared all the R17 coat protein sequence except that the seven NH2-terminal amino acids were missing. The minor product had the complete coat protein sequence starting from formylmethionine except for a probable amino acid substitution at codon 7 (UAG). Addition of RR factor inhibited the synthesis of the major protein. These results indicate that, in the absence of RR factor, the ribosome that has released the NH2-terminal hexapeptide at the amber codon stays on the mRNA and subsequently reinitiates translation "in phase" immediately after the amber codon without formylmethionine.

Amino Acid Sequence↗
PubMed1981

Nonrandom patterns of codon usage and of nucleotide substitutions in human alpha- and beta-globin genes: an evolutionary strategy reducing the rate of mutations with drastic effects?

Nucleotide substitutions within a structural gene can cause two principal "drastic" phenotypic effects at the protein level: translatable leads to untranslatable and nonpolar hydrophobic in equilibrium hydrophilic amino acid substitutions. The sequence of nucleotides in the structural human alpha- and beta-globin genes and their variants were examined to determine whether codon usage, patterns of nucleotide substitutions, or both, reduced the relative and absolute rates of these unfavorable mutations. Based on translation of abnormal hemoglobins, it is likely that all 61 nontermination codons are potentially translatable, though only 47 are normally used. Moreover, codons that can mutate to a termination codon are never used whenever the corresponding amino acid is specified also by triplets that cannot mutate to termination by a single-step mutation. Thus, the number of opportunities to mutate to an untranslatable codon is reduced to the minimum compatible with the amino acid composition of these chains. The relative rates of U in equilibrium non-U substitutions were much lower than those of other substitutions. Because U residues must be involved in most termination mutations and in all nonpolar hydrophobic in equilibrium hydrophilic amino acid substitutions, there is a considerable reduction of mutational events, causing drastic phenotypic effects. These findings are likely to be the end result of evolutionary selection by yet unknown mechanisms.

Base Sequence↗
PubMed1981

Extraordinarily high evolutionary rate of pseudogenes: evidence for the presence of selective pressure against changes between synonymous codons.

Comparisons of nucleotide sequences of several pseudogenes described to date, including alpha- and beta-globin and immunoglobulin kappa-type variable domain pseudogenes, with those of functional counterparts revealed that pseudogenes accumulate mutations at an extremely high rate uniformly over their entirety. It is remarkable that the evolutionary rate exceeds the rate of changes between synonymous codons, the highest known rate, in functional genes. Because no pseudogenes appear to function, this result strongly supports the neutral theory. In addition this result apparently indicates the presence of selective pressure against changes between synonymous codons in functional genes. Close examinations of codon utilization patterns in pseudogenes and functional genes revealed a significant correlation between the rate of changes at synonymous codon sites and the strength of bias in code word usage. This implies that even synonymous codon changes are not completely free from selective pressure but are constrained in part, although presumably weakly, depending on the degree of bias in code word usage. We also reexamined alignment between mouse beta h3 (pseudogene) and beta maj sequences and found a unique structure of the beta h3 that is homologous in sequence to the beta maj gene overall but contains a long deletion (about 150 base pairs) in the middle of the gene.

Animals↗
PubMed1986

Harvey ras genes transform without mutant codons, apparently activated by truncation of a 5' exon (exon -1).

The hypothesis is tested that the ras gene of Harvey sarcoma virus (Ha-SV) and the proto-ras DNAs from certain tumor cells derive transforming function from specific codons in which they differ from normal proto-ras genes. Molecularly cloned Harvey proviral vectors carrying viral ras, normal rat proto-ras, and recombinant ras genes in which the virus-specific ras codons 12 and 59 were replaced by proto-ras equivalents each transformed aneuploid mouse 3T3 cells after latent periods that ranged from 4 to 10 days. Viruses with or without virus-specific ras codons all transformed diploid rat cells in 3-5 days equally well. However, in the absence of virus replication, mutant codons were beneficial for transforming function. Deletion of non-ras regions of Ha-SV did not affect transforming function. We conclude that specific ras codons are not necessary for transforming function. Comparisons of the ras sequences of Ha-SV, BALB SV, and Rasheed SV with sequences of proto-ras genes from rat and man revealed an upstream proto-ras exon, termed exon -1. The 3' end of this exon is present in all three viruses and in a ras pseudogene of the rat. Since ras genes transform without mutation and since exon -1 is truncated in viral ras genes and all transforming proto-ras DNAs of the Harvey and the Kirsten ras family, we propose that ras genes are activated by truncation of exon -1 either via viral transduction or artificially via cloning and transfection. The proposal implies that untruncated proto-ras genes with point mutations may not be cellular cancer genes.

Animals↗
PubMed1988

Directional mutation pressure and transfer RNA in choice of the third nucleotide of synonymous two-codon sets.

Bacterial species have diverged into a series of families, some with high G + C content in their DNA, and other with high A + T content, resulting, respectively, from G.C- and A.T-directional mutation pressures. Such mutation pressure (G.C/A.T pressure) may be an important determinant for codon usage. It has also been suggested that tRNA acts as a selective constraint for determining codon usage. We have studied the relation between G.C/A.T pressure and tRNA constraints in determining choice of the third nucleotide of eight two-codon sets, using codon usage data obtained from protein genes in four bacterial species, Mycoplasma capricolum, Bacillus subtilis, Escherichia coli, and Micrococcus luteus, and in liverwort (Marchantia polymorpha) chloroplasts. The genomic G + C contents of these range from 25% to 74%. The results demonstrate that tRNA levels act additively to A.T and G.C pressure in affecting contents of A (pairing with *UNN anticodons, in which *U indicates a 2-thiouridine derivative) and C (pairing with GNN anticodons) or G (pairing with CNN anticodons), respectively, in third nucleotide positions of codons.

Chloroplasts↗
PubMed1990

Initiation of protein synthesis from a termination codon.

We show that the amber termination codon UAG can initiate protein synthesis in Escherichia coli. We mutated the initiation codon AUG of the chloramphenicol acetyltransferase (CAT) gene to UAG (CATam1) and translated mRNA derived from the mutant CAT gene in E. coli S-30 extracts. A full-length CAT polypeptide was synthesized in the presence of tRNA(fMetCUA), a mutant E. coli initiator tRNA which has a change in the anticodon sequence from CAU to CUA. Addition of purified E. coli glutaminyl-tRNA synthetase substantially stimulated synthesis of the CAT polypeptide. Thus, initiation of protein synthesis with UAG and tRNA(fMetCUA) most likely occurs with glutamine and not methionine. The UAG codon also initiates protein synthesis in vivo. To eliminate a weak secondary site of initiation from AUC, the fifth codon, we further mutagenized the CATam1 gene at codons 2 (GAG----GAC) and 5 (AUC----ACC). Transformation of E. coli with the resultant CATam1.2.5 gene yielded transformants that synthesized CAT polypeptide and were resistant to chloramphenicol only when they were also transformed with the mutant tRNA(fMetCUA) gene. Immunoblot analyses and assays for CAT enzyme activity in extracts from transformed cells indicate that initiation from UAG is efficient, 60-70% of that obtained from AUG. Initiation of protein synthesis from UAG using a mutant initiator tRNA allows tightly regulated expression of specific genes. This may be generally useful for overproduction in E. coli and other eubacteria of proteins which are toxic to these cells.

Anti-Bacterial Agents↗
PubMed1993

Aflatoxin B1 induces the transversion of G-->T in codon 249 of the p53 tumor suppressor gene in human hepatocytes.

Approximately half of hepatocellular carcinoma (HCC) from regions in the world with high contamination of food with the mycotoxin aflatoxin B1 (AFB1) contain a mutation in codon 249 of the p53 tumor suppressor gene. The mutation almost exclusively consists of a G-->T transversion in the third position of this codon, resulting in the insertion of serine at position 249 in the mutant protein. To gain insight into the mechanism of formation of this striking mutational hot spot in hepatocarcinogenesis, we studied the mutagenesis of codons 247-250 of p53 by rat liver microsome-activated AFB1 in human HCC cells HepG2 by restriction fragment length polymorphism/polymerase chain reaction genotypic analysis. AFB1 preferentially induced the transversion of G-->T in the third position of codon 249. However, AFB1 also induced G-->T and C-->A transversions into adjacent codons, albeit at lower frequencies. Since the latter mutations are not observed in HCC it follows that both mutability on the DNA level and altered function of the mutant serine 249 p53 protein are responsible for the observed mutational hot spot in p53 in HCC from AFB1-contaminated areas. Our results are in agreement with an etiological role of AFB1 in hepatocarcinogenesis in regions of the world with AFB1-contaminated food.

Aflatoxin B1↗
PubMed1993

Selection of CUG and AUG initiator codons for Drosophila E74A translation depends on downstream sequences.

Selection of a translation initiation site is thought to be determined by relative proximity to the 5' end and sequence context of a potential initiator codon. These guidelines seem insufficient to explain translation of the Drosophila E74A mRNA, whose 5' untranslated region is exceptionally long (1.8 kb) and contains many AUG triplets preceding the long open reading frame. In an effort to understand how the appropriate initiator codon is chosen, we have undertaken a study of E74A translation in transfected Drosophila cells. The results show that translation of the E74A protein utilizes at least three initiator codons: two minor forms of the protein are initiated at a CUG and an AUG, while the most abundant form initiates at a CUG. This main initiator CUG appears to be in a good context; however, it lies downstream of 17 AUG and 24 other CUG codons, several of which are also in good contexts. Unexpected results were obtained from sequence perturbations upstream and downstream of the main CUG initiator. Creating an AUG with a good context 72 bases 5' to the main CUG has only a modest inhibitory effect on initiation frequency at that CUG. Replacing sequences 44 bases 3' to the main CUG has an inhibitory effect on its use as an initiator as well as on the CUG 72 bases further upstream. These results indicate that factors other than context and relative proximity to the 5' end must be involved in initiator codon selection and may include elements such as secondary or tertiary structure of the RNA.

Amino Acid Sequence↗