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PubMed1990

Subcellular fate of the int-2 oncoprotein is determined by choice of initiation codon.

Fibroblast growth factors (FGFs) have been implicated in many aspects of cell growth and differentiation both in normal and neoplastic settings. For example, the mouse int-2 gene, which encodes an FGF-related product, is a frequent target of proviral activation in carcinomas induced by mouse mammary tumour virus, but apparently functions at discrete stages of normal embryonic development. Six classes of int-2 messenger RNA have been identified in embryonic cells, each of which is predicted to encode the same 245-amino-acid protein. But all known int-2 transcripts include sequences upstream of the AUG codon presumed to be the initiation codon. Here we report an additional N-terminally extended int-2 gene product initiated at an in-frame CUG codon. In COS-1 cells transiently transfected with appropriate int-2 complementary DNAs, the AUG-initiated product is found predominantly in the secretory pathway, whereas the CUG-initiated form is localized to the nucleus. These data indicate that the Int-2 oncoprotein could influence cellular behaviour by two distinct mechanisms.

Amino Acid Sequence↗
PubMed2000

A tripeptide 'anticodon' deciphers stop codons in messenger RNA.

The two translational release factors of prokaryotes, RF1 and RF2, catalyse the termination of polypeptide synthesis at UAG/UAA and UGA/UAA stop codons, respectively. However, how these polypeptide release factors read both non-identical and identical stop codons is puzzling. Here we describe the basis of this recognition. Swaps of each of the conserved domains between RF1 and RF2 in an RF1-RF2 hybrid led to the identification of a domain that could switch recognition specificity. A genetic selection among clones encoding random variants of this domain showed that the tripeptides Pro-Ala-Thr and Ser-Pro-Phe determine release-factor specificity in vivo in RF1 and RF2, respectively. An in vitro release study of tripeptide variants indicated that the first and third amino acids independently discriminate the second and third purine bases, respectively. Analysis with stop codons containing base analogues indicated that the C2 amino group of purine may be the primary target of discrimination of G from A. These findings show that the discriminator tripeptide of bacterial release factors is functionally equivalent to that of the anticodon of transfer RNA, irrespective of the difference between protein and RNA.

Amino Acid Sequence↗
PubMed1991

Recognition of UGA as a selenocysteine codon in type I deiodinase requires sequences in the 3' untranslated region.

Selenocysteine is incorporated cotranslationally at UGA codons, normally read as stop codons, in several bacterial proteins and in the mammalian proteins glutathione peroxidase (GPX), selenoprotein P and Type I iodothyronine 5' deiodinase (5'DI). Previous analyses in bacteria have suggested that a stem-loop structure involving the UGA codon and adjacent sequences is necessary and sufficient for selenocysteine incorporation into formate dehydrogenase and glycine reductase. We used the recently cloned 5'DI to investigate selenoprotein synthesis in eukaryotes. We show that successful incorporation of selenocysteine into this enzyme requires a specific 3' untranslated (3'ut) segment of about 200 nucleotides, which is found in both rat and human 5'DI messenger RNAs. These sequences are not required for expression of a cysteine-mutant deiodinase. Although there is little primary sequence similarity between the 3'ut regions of these mRNAs and those encoding GPX, the 3'ut sequences of rat GPX can substitute for the 5'DI sequences in directing selenocysteine insertion. Computer analyses predict similar stem-loop structures in the 3'ut regions of the 5'DI and GPX mRNAs. Limited mutations in these structures reduce or eliminate their capacity to permit 5'DI translation. These results identify a 'selenocysteine-insertion sequence' motif in the 3'ut region of these mRNAs that is essential for successful translation of 5'DI, presumably GPX, and possibly other eukaryotic selenocysteine-containing proteins.

Animals↗
PubMed1991

Early-onset Alzheimer's disease caused by mutations at codon 717 of the beta-amyloid precursor protein gene.

A mutation at codon 717 of the beta-amyloid precursor protein gene has been found to cosegregate with familial Alzheimer's disease in a single family. This mutation has been reported in a further five out of approximately 100 families multiply affected by Alzheimer's disease. We have identified another family, F19, in which we have detected linkage between the beta-amyloid precursor protein gene and Alzheimer's disease. Direct sequencing of exon 17 in affected individuals from this family has revealed a base change producing a Val----Gly substitution, also at codon 717. The occurrence of a second allelic variant at codon 717 linked to the Alzheimer's phenotype supports the hypothesis that they are pathogenic mutations.

Alzheimer Disease↗
PubMed1996

Codon 12 Ki-ras mutation in non-small-cell lung cancer: comparative evaluation in tumoural and non-tumoural lung.

Ki-ras activation by point mutation on codon 12 has been reported in non-small-cell lung carcinomas and in various models of experimental lung tumours induced by chemical carcinogens. The cellular targets for carcinogenic compounds of tobacco smoke are usually considered to be the cells of the bronchial mucosa or alveolar epithelium. However, little is known about preneoplastic events in bronchopulmonary carcinogenesis. The hypothesis of the presence of widespread target cells containing Ki-ras mutation was investigated by evaluating concurrent neoplastic and non-neoplastic bronchial and alveolar samples from 51 patients with non-small-cell lung carcinomas. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method used can detect one cell with a mutation on codon 12 among 10(2) normal cells. In tumour samples, a mutation was detected in 20% of adenocarcinomas, but in none of the adenosquamous or squamous cell carcinomas. No mutation was detected in the non-neoplastic bronchial or parenchymal samples. When using an enriched PCR-RFLP method detecting one mutated allele among 10(3) normal alleles a mutation was detected in 23% of adenocarcinomas. In conclusion, Ki-ras activation by mutation on codon 12 was not observed in non-neoplastic bronchial or parenchymal tissues in patients with bronchopulmonary cancers and does not appear to be a genetic event present in non-malignant epithelial target cells exposed to tobacco smoke.

Carcinoma, Non-Small-Cell Lung↗
PubMed1991

Evaluation of foreign gene codon optimization in yeast: expression of a mouse IG kappa chain.

We have optimized the codons in an immunoglobulin kappa chain gene to those preferred in the yeast Saccharomyces cerevisiae. The mutant and wild type kappa chain genes were each fused with a synthetic invertase signal peptide that also contained only yeast-preferred codons, and expressed in the F762 yeast strain. The use of yeast-preferred codons resulted in a more than 5-fold increase in the rate of synthesis and at least a 50-fold increase in the steady state level of protein.

Animals↗
PubMed2004

Streptomycin interferes with conformational coupling between codon recognition and GTPase activation on the ribosome.

Aminoacyl-tRNAs (aa-tRNAs) are selected by the ribosome through a kinetically controlled induced fit mechanism. Cognate codon recognition induces a conformational change in the decoding center and a domain closure of the 30S subunit. We studied how these global structural rearrangements are related to tRNA discrimination by using streptomycin to restrict the conformational flexibility of the 30S subunit. The antibiotic stabilized aa-tRNA on the ribosome both with a cognate and with a near-cognate codon in the A site. Streptomycin altered the rates of GTP hydrolysis by elongation factor Tu (EF-Tu) on cognate and near-cognate codons, resulting in almost identical rates of GTP hydrolysis and virtually complete loss of selectivity. These results indicate that movements within the 30S subunit at the streptomycin-binding site are essential for the coupling between base pair recognition and GTP hydrolysis, thus modulating the fidelity of aa-tRNA selection.

Binding Sites↗
PubMed2004

The role of modifications in codon discrimination by tRNA(Lys)UUU.

The natural modification of specific nucleosides in many tRNAs is essential during decoding of mRNA by the ribosome. For example, tRNA(Lys)(UUU) requires the modification N6-threonylcarbamoyladenosine at position 37 (t(6)A37), adjacent and 3' to the anticodon, to bind AAA in the A site of the ribosomal 30S subunit. Moreover, it can only bind both AAA and AAG lysine codons when doubly modified with t(6)A37 and either 5-methylaminomethyluridine or 2-thiouridine at the wobble position (mnm(5)U34 or s(2)U34). Here we report crystal structures of modified tRNA anticodon stem-loops bound to the 30S ribosomal subunit with lysine codons in the A site. These structures allow the rationalization of how modifications in the anticodon loop enable decoding of both lysine codons AAA and AAG.

Anticodon↗
PubMed2002

Association of p53 codon 72 polymorphism with advanced lung cancer: the Arg allele is preferentially retained in tumours arising in Arg/Pro germline heterozygotes.

The association of p53 codon 72 polymorphism with cancer has been investigated by several scientific groups with controversial results. In the present study, we examined the genotypic frequency of this polymorphism in 54 patients with advanced lung cancer and 99 normal controls from the geographical region of Greece. Sputum and bronchial washing samples from each patient were assayed for the presence of human papillomavirus. Codon 72 heterozygous (Arg/Pro) patients were also analysed for loss of heterozygosity at the TP53 locus, in order to determine the lost p53 allele (Arg or Pro). p53 Arg/Arg genotype was significantly increased in lung cancer patients compared to normal controls (50% vs 24.2%, P<0.002). Human papillomavirus was detected only in two patients (3.7%). Loss of heterozygosity at the TP53 locus was found in 14 out of 27 Arg/Pro patients (51.85%). The Pro allele was lost in 11 cases (78.6%), while the Arg allele was lost in three (21.4%). Our results suggest that p53 codon 72 Arg homozygosity is associated with advanced lung cancer, and that the Arg allele is preferentially retained in patients heterozygous for this polymorphism. On the other hand, human papillomavirus infection does not seem to play an important role in lung carcinogenesis.

Aged↗
PubMed2004

The different apoptotic potential of the p53 codon 72 alleles increases with age and modulates in vivo ischaemia-induced cell death.

A common arginine to proline polymorphism is harboured at codon 72 of the human p53 gene. In this investigation, we found that fibroblasts and lymphocytes isolated from arginine allele homozygote centenarians and sexagenarians (Arg+) undergo an oxidative-stress-induced apoptosis at a higher extent than cells obtained from proline allele carriers (Pro+). At variance, the difference in apoptosis susceptibility between Arg+ and Pro+ is not significant when cells from 30-year-old people are studied. Further, we found that Arg+ and Pro+ cells from centenarians differ in the constitutive levels of p53 protein and p53/MDM2 complex, as well as in the levels of oxidative stress-induced p53/Bcl-xL complex and mitochondria-localised p53. Consistently, all these differences are less evident in cells from 30-year-old people. Finally, we investigated the in vivo functional relevance of the p53 codon 72 genotype in a group of old patients (66-99 years of age) affected by acute myocardial ischaemia, a clinical condition in which in vivo cell death occurs. We found that Arg+ patients show increased levels of Troponin I and CK-MB, two serum markers that correlate with the extent of the ischaemic damage in comparison to Pro+ patients. In conclusion, these data suggest that p53 codon 72 polymorphism contributes to a genetically determined variability in apoptotic susceptibility among old people, which has a potentially relevant role in the context of an age-related pathologic condition, such as myocardial ischaemia.

Adult↗
PubMed2005

Ribosome bypassing at serine codons as a test of the model of selective transfer RNA charging.

Recently, a model of the flux of amino acids through transfer RNAs (tRNAs) and into protein has been developed. The model predicts that the charging level of different isoacceptors carrying the same amino acid respond very differently to variation in supply of the amino acid or of the rate of charging. It has also been shown that ribosome bypassing is specifically stimulated at 'hungry' codons calling for an aminoacyl-tRNA in short supply. We have constructed two reporters of bypassing, which differ only in the identity of the serine codon subjected to starvation. The stimulation of bypassing as a function of starvation differed greatly between the two serine codons, in good agreement with the quantitative predictions of the model.

Codon↗
PubMed1999

Over-representation of a germline RET sequence variant in patients with sporadic medullary thyroid carcinoma and somatic RET codon 918 mutation.

The aetiology of sporadic medullary thyroid carcinoma is unknown. About 50% harbour a somatic mutation at codon 918 of RET (M918T). To investigate whether other RET sequence variants may be associated with or predispose to the development of sporadic medullary thyroid carcinoma, we analysed genomic DNA from the germline and corresponding tumour from 50 patients to identify RET sequence variants. In one patient, tumour DNA showed a novel somatic 12 bp in-frame deletion in exon 15. More interestingly, we found that the rare polymorphism at codon 836 (c.2439C > T; S836S) occurred at a significantly higher frequency than that in control individuals without sporadic medullary thyroid carcinoma (Fisher's exact test, P = 0.03). Further, among the nine evaluable cases with germline c.2439C/T, eight also had the somatic M918T mutation in MTC DNA which was more frequent than in patients with the more common c.2439C/C (89% vs 40%, respectively; Fisher's exact test, P = 0.01). These findings suggest that the rare sequence variant at codon 836 may somehow play a role in the genesis of sporadic medullary thyroid carcinoma.

Carcinoma, Medullary↗
PubMed1999

Alternate choice of initiation codon produces a biologically active product of the von Hippel Lindau gene with tumor suppressor activity.

The VHL tumor suppressor gene has previously been reported to encode a protein of 213 amino acid residues. Here we report the identification of a second major VHL gene product with an apparent molecular weight of 18 kD, pVHL18, which appears to arise from alternate translation initiation at a second AUG codon (codon 54) within the VHL open reading frame. In vitro and in vivo studies indicate that the internal codon in the VHL mRNA is necessary and sufficient for production of pVHL18. pVHL18 can bind to elongin B, elongin C, and Hs-CUL2. When reintroduced into renal carcinoma cells that lack a wild-type VHL allele, pVHL18 suppresses basal levels of VEGF expression, restores hypoxia-inducibility of VEGF expression, and inhibits tumor formation in nude mice. These data strongly support the existence of two distinct VHL gene products in VHL tumor suppression.

Animals↗
PubMed2004

Functional polypeptides can be synthesized from human mitochondrial transcripts lacking termination codons.

The human mitochondrial genome (mtDNA) is a small, circular DNA duplex found in multi-copy in the mitochondrial matrix. It is almost fully transcribed from both strands to produce large polycistronic RNA units that are processed and matured. The 13 mtDNA-encoded polypeptides are translated from mt-mRNAs that have been matured by polyadenylation of their free 3'-termini. A patient with clinical features consistent with an mtDNA disorder was recently shown to carry a microdeletion, resulting in the loss of the termination codon for MTATP6 and in its juxtaposition with MTCO3. Cell lines from this patient exhibited low steady-state levels of RNA14, the bi-cistronic transcript encoding subunits 6 and 8 of the F(o)F(1)-ATP synthase, complex V, consistent with a decreased stability. Recent reports of 'non-stop' mRNA decay systems in the cytosol have failed to determine the fate of gene products derived from transcripts lacking termination codons, although enhanced decay clearly required the 'non-stop' transcripts to be translated. We wished to determine whether functional translation products could still be expressed from non-stop transcripts in the human mitochondrion. Although a minor defect in complex V assembly was noted in the patient-derived cell lines, the steady-state level of ATPase 6 was similar to controls, consistent with the pattern of de novo mitochondrial protein synthesis. Moreover, no significant difference in ATP synthase activity could be detected. We conclude that, in the absence of a functional termination codon, although mitochondrial transcripts are more rapidly degraded, they are also translated to generate stable polypeptides that are successfully integrated into functional enzyme complexes.

Adenosine Triphosphatases↗
PubMed2004

Choice of a start codon in a single transcript determines DNA ligase 1 isoform production and intracellular targeting in Arabidopsis thaliana.

DNA ligase 1 (AtLIG1) is the only essential DNA ligase activity in Arabidopsis and is implicated in the important processes of DNA replication, repair and recombination and in transgene insertion during Agrobacterium-mediated plant transformations. The mitochondrial and nuclear forms of DNA ligase 1 in Arabidopsis are translated from a single mRNA species through the control of translation initiation from either the first (M1) or second (M2) in-frame AUG codons respectively. Translation from a third in-frame AUG codon (M3) occurs on transcripts in which M1 and M2 are mutagenized to stop codons. Wild-type AtLIG1-GFP constructs (where GFP stands for green fluorescent protein) can be targeted in planta to both the nucleus and mitochondria. AtLIG1-GFP translation from M1 specifically targets the fusion protein only to mitochondria in planta, whereas translation from M2 or M3 targets the fusion protein only to the nucleus. Interestingly, the AtLIG1-GFP fusion protein in which translation is initiated from M1 contains both an N-terminal mtPS (mitochondrial targeting presequence) and a nuclear localization signal; nonetheless, this protein is only targeted to the mitochondria. This result raises intriguing questions on the translational control mechanisms that regulate how the protein products of a single transcript are targeted to more than one cellular compartment.

Amino Acid Sequence↗
PubMed2002

The influence of the polymorphism in apolipoprotein B codon 2488 on insulin and lipid levels in a Danish twin population.

AIMS: The apolipoprotein B codon 2488 polymorphism has been associated with the metabolism of lipoproteins in subjects with Type 2 diabetes. However, no data are available on the influence of the polymorphism on insulin or glucose metabolism. This study examines the impact of the polymorphism on parameters associated with the insulin resistance syndrome in Danish twins. METHODS: The effect of the polymorphism on lipid, glucose and insulin measures was studied in 548 same sex twins aged 55-74 years. RESULTS: The codon 2488 polymorphism influenced fasting triglyceride levels, as well as insulin, as measured at 120 min in an oral glucose tolerance test. Subjects with the genotype T2488T had 14% higher triglyceride levels (P = 0.02) and 31% higher insulin levels (P = 0.004) than subjects with genotype C2488C. In twins discordant for genotype, the T-allele was associated with higher levels of triglyceride (P = 0.04) and insulin (P = 0.02) and lower levels of HDL-cholesterol (P = 0.04). CONCLUSION: The T-allele of the codon 2488 polymorphism influenced parameters related to the insulin resistance syndrome, i.e. increased levels of insulin, increased levels of triglyceride and decreased levels of HDL. As the polymorphism is silent, these effects must be mediated through linkage to other polymorphisms in apolipoprotein B or other genes on chromosome 2.

Aged↗
PubMed1998

How protein reads the stop codon and terminates translation.

Translation termination requires two codon-specific protein-release factors in prokaryotes and one factor in eukaryotes. The underlying mechanism for stop codon recognition, as well as the biological meaning of the conservation of one or two release factors in the evolutionary kingdoms, are not known. The recent discovery of release factor genes and the molecular mimicry between translational factors and tRNA provide us with clues to the mechanisms of how proteins read the stop codon and terminate translation, shedding some light on the evolutionary aspect of release factors.

Amino Acid Sequence↗
PubMed1999

Amber (UAG) suppressors affected in UGA/UAA-specific polypeptide release factor 2 of bacteria: genetic prediction of initial binding to ribosome preceding stop codon recognition.

BACKGROUND: Prokaryotic translational release factors, RF1 and RF2, catalyse protein release at UAG/UAA and UGA/UAA stop codons, respectively. Mutations in RF1 and RF2 are known to cause non-sense suppression for UAG (amber) and UGA (opal) codons, respectively, and they do not exert a reciprocal ('cross') suppression phenotype. We aimed to isolate RF mutants of such cross-suppression activity, which we designated 'Csu' phenotype in this paper. RESULTS: Using a lacZ (UAG) reporter, we selected amber suppressor alleles occurring in the plasmid-bearing RF2 gene of Salmonella typhimurium. Of nine such RF2 csu alleles, five were mis-sense mutations and four were non-sense mutations. The former mis-sense mutants retained the RF2 activity and catalysed UGA termination both in vivo and in vitro. RF2 C-terminal deletions equivalent to the non-sense alleles exerted amber suppression as well as opal suppression activity. Moreover, the equivalent RF1 segments also showed both the suppression phenotypes. CONCLUSIONS: All the csu mutations were mapped at the C-terminal half of RF2 and are strikingly coincident with the highly conservative amino acids, suggesting that they affect the conserved function of bacterial RFs. We propose here that there should be an 'initial binding' step of RFs to the ribosome, preceding stop codon recognition ('initial binding' hypothesis) and that the N-terminal RF domain(s), that are truncated or affected by the csu mutations, are responsible for this step and interfere with the proper functioning of cognate release factors on the ribosome.

Alleles↗