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PubMed2001

Association of the vitamin D receptor gene start codon Fok I polymorphism with calcium oxalate stone disease.

OBJECTIVE: To assess the use of Fok I polymorphism (the most frequent polymorphism, at the start codon of the vitamin D receptor gene, VDR) as a convenient genetic marker in identifying the cause of urolithiasis. PATIENTS, SUBJECTS AND METHODS: A normal control group of 90 healthy subjects and 146 patients with calcium oxalate stones were examined. Using polymerase chain reaction (PCR)-based restriction analysis, the relationship between Fok I polymorphism and urolithiasis was evaluated. An unexcisable length of 265 bp was identified (allele CC) and two fragments (169 bp and 96 bp) identified as excisable lengths (allele TT). RESULTS: There was a statistically significant difference between the groups (chi-square test, P < 0.05) for the genotype of the VDR Fok I start codon polymorphism. The odds ratio (95% confidence interval) for the C allele in those at risk of stone disease was 1.672 (1.149-2.432). CONCLUSIONS: These results suggest that the VDR Fok I start codon polymorphism may be a good candidate for a genetic marker in calcium oxalate stone disease.

Adult↗

PubMed2006

Specific use of start codons and cellular localization of splice variants of human phosphodiesterase 9A gene.

BACKGROUND: Phosphodiesterases are an important protein family that catalyse the hydrolysis of cyclic nucleotide monophosphates (cAMP and cGMP), second intracellular messengers responsible for transducing a variety of extra-cellular signals. A number of different splice variants have been observed for the human phosphodiesterase 9A gene, a cGMP-specific high-affinity PDE. These mRNAs differ in the use of specific combinations of exons located at the 5' end of the gene while the 3' half, that codes for the catalytic domain of the protein, always has the same combination of exons. It was observed that to deduce the protein sequence with the catalytic domain from all the variants, at least two ATG start codons have to be used. Alternatively some variants code for shorter non-functional polypeptides. RESULTS: In the present study, we expressed different splice variants of PDE9A in HeLa and Cos-1 cells with EGFP fluorescent protein in phase with the catalytic domain sequence in order to test the different start codon usage in each splice variant. It was found that at least two ATG start codons may be used and that the open reading frame that includes the catalytic domain may be translated. In addition the proteins produced from some of the splice variants are targeted to membrane ruffles and cellular vesicles while other variants appear to be cytoplasmic. A hypothesis about the functional meaning of these results is discussed. CONCLUSION: Our data suggest the utilization of two different start codons to produce a variety of different PDE9A proteins, allowing specific subcellular location of PDE9A splice variants.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed1996

RNA phage KU1 has an insertion of 18 nucleotides in the start codon of its lysis gene.

We have determined the nucleotide sequence of group II RNA phage KU1. The most conspicuous difference in the comparison with other group II members such as GA and JP34 is the presence of an insertion in the start codon of the lysis gene. In GA and JP34, the coat and lysis genes overlap by one nucleotide in the configuration UAAUG. The 18-nt insertion in KU1 is positioned between the A and the U of the start codon. It does not affect the coat reading frame, but it destroys the AUG start codon and separates the previously overlapping genes by 17 nts. The insert creates a UUG codon at its 3' border which serves as the start site for lysis protein synthesis in KU1. We also show that analogous to the group I phages, such as MS2 and fr, expression of the lysis gene in KU1 and JP34 is coupled to termination of translation at the coat gene. RNA secondary structure models for the central parts of KU1 and JP34 are suggested which can account for the insertion as a separate stem-loop structure.

Base Sequence↗

PubMed1993

Control of start codon choice on a plant viral RNA encoding overlapping genes.

The signals that control initiation of translation in plants are not well understood. To dissect some of these signals, we used a plant viral mRNA on which protein synthesis initiates at two out-of-frame start codons. On the large subgenomic RNA (sgRNA1) of barley yellow dwarf virus-PAV serotype, the coat protein (CP) and overlapping 17K open reading frames (ORFs) are translated beginning at the first and second AUG codons, respectively. The roles of bases at positions -3 and +4 relative to the AUG codons in efficiency of translation initiation were investigated by translation of sgRNA1 mutants in a cell-free extract and by expression of a reporter gene from mutant sgRNA1 leaders in protoplasts. The effects of mutations that disrupted and restored secondary structure encompassing the CP AUG independently of, and in combination with, changes to bases -3 and +4 were also examined. Partial digestion of the 5' end of the sgRNA1 leader with structure-sensitive nucleases gave products that were consistent with the predicted secondary structure. Secondary structure had an overall inhibitory effect on translation of both ORFs. In general, the "Kozak rules" of start codon preference predominate in determining start codon choice. Unexpectedly, for a given CP AUG sequence context, changes that decreased initiation at the downstream 17K AUG also reduced initiation at the CP AUG. To explain this observation, we propose a new model in which pausing of the ribosome at the second AUG allows increased initiation at the first AUG. This detailed analysis of the roles of primary and secondary structure in controlling translation initiation should be of value for understanding expression of any plant gene and in the design of artificial constructs.

Animals↗

PubMed2003

[Study on the distribution of vitamin D receptor gene start codon polymorphism in the Achangs and Hans].

OBJECTIVE: To detect the difference between the Chinese Achang and Han ethnic groups in Yunnan province in the distribution of vitamin D receptor (VDR) gene start codon polymorphism. METHODS: Polymerase chain reaction-restriction fragment length polymorphism, gene sequencing and genetic analysis methods were used. A restriction fragment length polymorphism in the start codon of VDR (Fok I) gene was tested in the Achangs (n=68) and the Hans (n=92). RESULTS: The frequencies of FF, Ff and ff genotypes were found to be 18%, 35% and 47% in the Achangs, and 22%, 52% and 26% in the Hans, respectively. A significant difference was seen in the frequency distribution of VDR genotype between the Achangs and the Hans(Chi2=7.716, P=0.021). CONCLUSION: The Achang and Han ethnic groups differ in the frequency distribution of VDR gene start codon polymorphism.

China↗

PubMed1999

A new 34-kilodalton isoform of human fibroblast growth factor 2 is cap dependently synthesized by using a non-AUG start codon and behaves as a survival factor.

Four isoforms of human fibroblast growth factor 2 (FGF-2) result from alternative initiations of translation at three CUG start codons and one AUG start codon. Here we characterize a new 34-kDa FGF-2 isoform whose expression is initiated at a fifth initiation codon. This 34-kDa FGF-2 was identified in HeLa cells by using an N-terminal directed antibody. Its initiation codon was identified by site-directed mutagenesis as being a CUG codon located at 86 nucleotides (nt) from the FGF-2 mRNA 5' end. Both in vitro translation and COS-7 cell transfection using bicistronic RNAs demonstrated that the 34-kDa FGF-2 was exclusively expressed in a cap-dependent manner. This contrasted with the expression of the other FGF-2 isoforms of 18, 22, 22.5, and 24 kDa, which is controlled by an internal ribosome entry site (IRES). Strikingly, expression of the other FGF-2 isoforms became partly cap dependent in vitro in the presence of the 5,823-nt-long 3' untranslated region of FGF-2 mRNA. Thus, the FGF-2 mRNA can be translated both by cap-dependent and IRES-driven mechanisms, the balance between these two mechanisms modulating the ratio of the different FGF-2 isoforms. The function of the new FGF-2 was also investigated. We found that the 34-kDa FGF-2, in contrast to the other isoforms, permitted NIH 3T3 cell survival in low-serum conditions. A new arginine-rich nuclear localization sequence (NLS) in the N-terminal region of the 34-kDa FGF-2 was characterized and found to be similar to the NLS of human immunodeficiency virus type 1 Rev protein. These data suggest that the function of the 34-kDa FGF-2 is mediated by nuclear targets.

3T3 Cells↗

PubMed2004

Compositional nonrandomness upstream of start codons in archaebacteria.

Since the regions directing transcriptional and translational initiation in archaebacteria are poorly characterized, the purpose of this study was to characterize them using measurements of nonrandomness upstream of start codons on eight fully sequenced archaebacterial genomes. Two distinctly different regions with conservation were identified. The location of the first corresponded well to the classical Shine-Dalgarno region (phi peak), and the other was located approximately 20-35 nucleotides upstream of start codons (alpha region), but both regions are not present in all strains. The composition of the region around the phi peak showed an overrepresentation of guanine, whereas composition in the alpha region had an overrepresentation of adenine and thymine. It is furthermore shown that the alpha region surprisingly is associated with start codon usage and other characteristics of the genes. The alpha region is likely to correspond to TATA-boxes and thereby indicates use of leaderless (or short-leadered) transcripts.

5' Flanking Region↗

PubMed1990

The psbC start codon in Synechocystis sp. PCC 6803.

The translation start codon for psbC, the gene encoding CP43, a chlorophyll-binding protein of photosystem II, has been identified for the cyanobacterium Synechosystis sp. PCC 6803 using site-directed mutagenesis. An AUG codon, about 50 bases upstream from the end of psbD-I had previously been assumed to be the translation start site of psbC. However, the fact that the AUG codon is not present in psbC from several other organisms, whereas a GUG codon 14 bases upstream from the end of psbD-I is strictly conserved suggests that CP43 translation starts at the latter codon. Mutation of GUG, but not of AUG, led to a loss of CP43 and photoautotrophic growth, indicating that the GUG codon is the sole initiation site for translation of the CP43 protein in Synechocystis sp. PCC 6803.

Base Sequence↗

PubMed2002

Relation of vitamin D receptor FokI start codon polymorphism to bone mineral density and occurrence of osteoporosis in postmenopausal women in Taiwan.

BACKGROUND: Osteoporosis is a common disorder with a strong genetic component. Our aim was to evaluate the correlation of the vitamin D receptor FokI start codon polymorphism to bone mineral density and the occurence of osteoporosis. METHODS: We determined the vitamin D receptor FokI start codon polymorphism using polymerase chain reaction-based restriction analysis in 163 postmenopausal women in Taiwan. The vitamin D receptor gene polymorphism was detected by the restriction enzyme FokI, where the F allele indicated the absence of the cuttable site and the f allele its presence. We then related the genotypes to bone mineral density and the occurence of osteoporosis in these women. RESULTS: The allelic frequencies for 163 postmenopausal women in Taiwan were 59.2% for F and 40.8% for f in FokI restriction fragment length polymorphisms. The prevalence of each genotype in the study population was: 42.3% FF, 33.7% Ff and 24% ff. The three genotypic groups differed significantly in bone mineral density at the lumbar spine (P = 0.029). Bone mineral density was highest in the Ff group and lowest in the ff group at the lumbar spine and the femoral neck. The FokI vitamin D receptor genotype showed a significant effect on the prevalence of osteoporosis in the subjects at the lumbar spine. That is, women with genotype ff had a 2.8 times greater risk for osteoporosis (P < 0.05), and those with genotype FF had a 0.8 times greater risk than women with genotype Ff. CONCLUSION: Our findings indicate that the vitamin D receptor FokI start codon polymorphism is associated with reduced bone mineral density and predisposes women to osteoporosis at the lumbar spine.

Alleles↗

PubMed1984

Mutagenesis of the three bases preceding the start codon of the beta-galactosidase mRNA and its effect on translation in Escherichia coli.

The effect on the translation efficiency of various mutations in the three bases (the -1 triplet) that precede the AUG start codon of the beta-galactosidase mRNA in Escherichia coli was studied. Of the 39 mutants examined, the level of expression varies over a 20-fold range. The most favorable combinations of bases in the -1 triplet are UAU and CUU. The expression levels in the mutants with UUC, UCA or AGG as the -1 triplet are 20-fold lower than those with UAU or CUU. In general, a U residue immediately preceding the start codon is more favorable for expression than any other base; furthermore, an A residue at the -2 position enhances the translation efficiency in most instances. In both cases, however, the degree of enhancement depends on its context, i.e. the neighboring bases. Although the rules derived from this study are complex, the results show that mutations in any of the three bases preceding the start codon can strongly affect the translational efficiency of the beta-galactosidase mRNA.

Base Sequence↗

PubMed1989

Putative start codon TTG for the regulatory protein VirG of the hairy-root-inducing plasmid pRiA4.

The nucleotide sequence of the virG gene for a transcriptional activator on the agropine-type hairy-root-inducing plasmid pRiA4 was determined. The sequence contained one possible open reading frame. The gene product with a molecular size of 26.5 kDa was identified by an Escherichia coli coupled-transcription-translation system using cloned virG plasmids as templates. However, neither an ATG nor a GTG start codon which could give rise to such a protein was identified in the nucleotide sequence. Instead, TTG was found as a candidate for the start codon. This TTG was preceded, like most other TTG start codons, by both a Shine-Dalgarno (SD) sequence and a T signal which are respectively complementary to the 3'-end region of 16S rRNA and the T psi loop of initiator tRNA. Further evidence for the start at TTG was obtained by gene fusion experiments. When the E. coli lacZ gene, whose expression entirely depends on the transcription and translation from upstream regions, was connected in-phase with virG either directly upstream or downstream of the TTG sequence, only the latter fused gene expressed the beta-galactosidase activity in Agrobacterium cells in response to a plant phenolic compound, acetosyringone. The TTG codon preceded by an SD sequence and a T signal is also conserved in the virG sequences from other three tumor-inducing plasmids previously reported.

Amino Acid Sequence↗

PubMed2003

A mutation at the start codon defines the differential requirement of dpy-11 in Caenorhabditis elegans body hypodermis and male tail.

dpy-11 encodes a thioredoxin-like molecule that is important for both body and male sensory ray morphogenesis in Caenorhabditis elegans. A mutant allele, s287, has a point mutation with its start codon, AUG, converted into AUA, presumably leading to null function. Since only a weak loss-of-function phenotype was observed, we tested whether an alternative start codon or the converted AUA could be used for translation initiation with reduced efficiency. Based on a functional assay of mutant phenotype complementation and biochemical analysis examining the in vivo synthesis of wild-type and mutant proteins, we conclude that AUA can be used as a less-efficient start codon for initiating translation of DPY-11. Our results also provide direct evidence that the body hypodermis and male tail of C. elegans have differential requirements of dpy-11 activity for their respective normal morphogenesis.

Alleles↗

PubMed1980

Initiation of protein synthesis in bacteria at a translational start codon of mamalian cDNA: effects of the preceding nucleotide sequence.

Plasmids containing a mouse cDNA sequence encoding the enzyme dihydrofolate reductase (DHFR; tetrahydrofolate dehydrogenase; 5,6,7,8-tetrahydrofolate:NADP+ oxidoreductase, EC 1.5.1.3) have been used to study the efficiency of initiation of protein synthesis at an ATG (AUG) translational start codon indigenous to the eukaryotic CDNA. differences in DHFR production assayed phenotypically, enzymatically, and immunologically were correlated with the primary structure of the DNA segment that precedes the translational start codon. Our results indicate that initiation of a structurally discrete and biologically functional eukaryotic protein can occur in bacteria on a fused mRNA molecule, and that the efficiency of expression is strongly affected by: (i) the extent of homology of the translational control region with the 3'-OH end of 16S ribosomal RNA, and (ii) the distance between the protein start codon and the ribosome-binding sequence on the mRNA.

Animals↗

PubMed2005

Start codon polymorphisms in the vitamin D receptor and colorectal cancer risk.

The expression of the nuclear vitamin D receptor (VDR), which is involved in regulating cell growth and proliferation, may contribute to the development of colorectal cancer. Polymorphisms in the VDR gene (OMIM 601769) may influence the expression or function of the VDR protein. A population-based, case-control study of VDR start codon, intron, and exon polymorphisms, haplotypes for these polymorphisms, and the relationships between these polymorphisms and clinicopathological parameters in 190 colorectal cancer patients and 318 controls was conducted. The start codon variant VDR 27823*C/*C genotype was associated with an increased risk for colorectal cancer, while the 27823*T/*T genotype was associated with a decreased risk. In addition, the VDR 61888*G/*G genotype was associated with reduced colorectal cancer risk. The intron 8 60880G>A and exon 9 61968T>C polymorphisms were not associated with colorectal cancer risk. The VDR 27823*C-60890*G-61888*T-61968*T haplotype was associated with an increased risk of colorectal cancer, whereas the VDR 27823*T-60890*G-61888*G-61968*T haplotype was associated with a decreased risk of colorectal cancer. Moreover, the 27823*C/*C genotype was more frequently identified in patients with preoperative serum carcinoembryonic antigen (CEA) levels over 6ng/mL. These results suggest that the VDR start codon 27823*C allele may be linked to high risk for colorectal cancer, especially in a subset of colorectal cancers showing specific biological behaviors.

Adult↗

PubMed2005

A cytosine-rich region upstream of start codons serving as a signal for initiation of translation in Encephalitozoon cuniculi?

Encephalitozoon cuniculi, an intracellular eukaryote frequently infecting immunodeficient humans, displays pronounced compaction in its genes. Short-leaded mRNA has been observed which has led to speculation into alternative mechanisms of translation initiation. It has been proposed that a 'downstream box' could serve as an initiation signal. In this report, non-randomness analysis was used to study the genes of E. cuniculi. Surprisingly, it was found that the region 5-10nt upstream of start codons is highly cytosine-enriched and this phenomenon clearly differentiates genes of predicted high and low expressivity. These two groups of genes can, on the other hand, not be clearly differentiated from non-randomness plots downstream of their start codons. The data thus do not support the 'downstream box' hypothesis but seem to suggest that initiation is depending on the region immediately upstream of start codons. The cytosine richness has no known parallel in other eukaryotes, prokaryotes or archaebacteria.

Animals↗

PubMed2005

Eukaryotic translational coupling in UAAUG stop-start codons for the bicistronic RNA translation of the non-long terminal repeat retrotransposon SART1.

Most eukaryotic cellular mRNAs are monocistronic; however, many retroviruses and long terminal repeat (LTR) retrotransposons encode multiple proteins on a single RNA transcript using ribosomal frameshifting. Non-long terminal repeat (non-LTR) retrotransposons are considered the ancestor of LTR retrotransposons and retroviruses, but their translational mechanism of bicistronic RNA remains unknown. We used a baculovirus expression system to produce a large amount of the bicistronic RNA of SART1, a non-LTR retrotransposon of the silkworm, and were able to detect the second open reading frame protein (ORF2) by Western blotting. The ORF2 protein was translated as an independent protein, not as an ORF1-ORF2 fusion protein. We revealed by mutagenesis that the UAAUG overlapping stop-start codon and the downstream RNA secondary structure are necessary for efficient ORF2 translation. Increasing the distance between the ORF1 stop codon and the ORF2 start codon decreased translation efficiency. These results are different from the eukaryotic translation reinitiation mechanism represented by the yeast GCN4 gene, in which the probability of reinitiation increases as the distance between the two ORFs increases. The translational mechanism of SART1 ORF2 is analogous to translational coupling observed in prokaryotes and viruses. Our results indicate that translational coupling is a general mechanism for bicistronic RNA translation.

Amino Acid Sequence↗

PubMed1999

Translation initiation factor 3 antagonizes authentic start codon selection on leaderless mRNAs.

In this study, we have examined the influence of initiation factors on translation initiation of leaderless mRNAs whose 5'-terminal residues are the A of the AUG initiating codon. A 1:1 ratio of initiation factors to ribosomes abolished ternary complex formation at the authentic start codon of different leaderless mRNAs. Supporting this observation, in vitro translation assays using limiting ribosome concentrations with competing leaderless lambda cl and Escherichia coli ompA mRNAs, the latter containing a canonical ribosome binding site, revealed reduced cl synthesis relative to OmpA in the presence of added initiation factors. Using in vitro toeprinting and in vitro translation assays, we show that this effect can be attributed to IF3. Moreover, in vivo studies revealed that the translational efficiency of a leaderless reporter gene is decreased with increased IF3 levels. These studies are corroborated by the observed increased translational efficiency of a leaderless reporter construct in an infC mutant strain unable to discriminate against non-standard start codons. These results suggest that, in the absence of a leader or a Shine-Dalgarno sequence, the function(s) of IF3 limits stable 30S ternary complex formation.

5' Untranslated Regions↗

PubMed1996

Ferritin translation by interleukin-1and interleukin-6: the role of sequences upstream of the start codons of the heavy and light subunit genes.

Interleukin-1beta (IL-1beta) elevates H- and L-ferritin subunit synthesis in both human hepatoma cells (HepG2) and primary human umbilical vein endothelial cells. Ferritin induction is greater than the increase in total HepG2 protein synthesis in response to IL-1. IL-6 causes a moderate increase in L-subunit synthesis. The levels of the mRNAs for the ferritin H-subunits (H-mRNA) and light subunits (L-mRNA) remain unchanged, indicating that expression of the iron storage protein, ferritin, is regulated by translational mechanisms during inflammation. We have found a translational enhancer region in the L-ferritin mRNA 5'UTR that confers two-fold baseline and twofold IL-1-dependent translational regulation to a CAT reporter message. The L-mRNA motif is related to a 61 nucleotide (nt) G+C-rich translational enhancer within 70 nt of the H-ferritin start codon. Sequences upstream of the start codons (SUS elements) in both H-mRNA and L-mRNAs confer IL-1beta but not IL-6-dependent translation to hybrid ferritin/CAT reporter mRNAs. The H- and L-ferritin mRNA SUS elements contain a motif similar to a consensus reported for the 5' leaders of other acute phase response mRNAs. Transfected hybrid H-mRNA SUS/CAT mRNAs with a three nucleotide deleted version of the H-mRNA SUS displays an eightfold reduced level of translation and no longer confer IL-1beta-dependent translation.

Acute-Phase Reaction↗