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PubMed2002

Cloning and characterization of the rat multidrug resistance-associated protein 1.

Multidrug resistance-associated protein 1 (MRP1) was originally shown to confer resistance of human tumor cells to a broad range of natural product anticancer drugs. MRP1 has also been shown to mediate efflux transport of glutathione and glucuronide conjugates of drugs and endogenous substrates. An ortholog of MRP1 in the mouse has been cloned and characterized. Significant functional differences between murine and human MRP1 have been noted. Since drug disposition and pharmacology studies often are conducted in rats, there is a need to clone and characterize the rat ortholog of MRP1. We isolated a rat MRP1 (rMRP1) cDNA from rat brain astrocytes, characterized its coding sequences, and verified the transport activity of the protein expressed in MRP1 cDNA-transfected Madin-Darby canine kidney (MDCK) cells. Our results showed that rMRP1 has a coding sequence of 4599 bp, which predicts a polypeptide of 1533 amino acids with an apparent molecular weight of 190 kd by Western immunoblot analysis. rMRP1-transfected MDCK cells are capable of efflux transport of a fluorescent MRP1 marker - calcein - that is inhibitable by known MRP1 inhibitors, indomethacin, and MK571. Sequence analysis indicates that rMRP1 is more closely related to mouse MRP1 than human MRP1.

Amino Acid Sequence↗
PubMed1995

Cysteine-to-arginine point mutation in a 'hybrid' eight-cysteine domain of FBN1: consequences for fibrillin aggregation and microfibril assembly.

Mutations in the FBN1 gene encoding the microfibrillar glycoprotein fibrillin cause Marfan syndrome, a relatively common autosomal dominant connective tissue disease. Causative FBN1 mutations appear to be dispersed throughout the coding frame, and to date no predictable genotype: phenotype correlations have emerged. We have identified a point mutation within an eight-cysteine 'hybrid' motif of the fibrillin polypeptide which results in the substitution of an arginine for a cysteine, in a patient severely affected in the cardiovascular, skeletal and ocular systems. We have utilised cell cultures from various tissues of this patient to investigate the effects of this mutation on fibrillin expression and deposition, and the consequences in terms of microfibril assembly and organisation. We have established that there is no difference in the expression of normal and mutant alleles, and fibrillin synthesis, secretion and deposition are also normal. However, the rate of fibrillin aggregation is reduced and microfibrillar assemblies are both remarkably scarce and morphologically abnormal. These data clearly demonstrate that the mutated allele interferes with normal assembly, and strongly implicate this particular region of the fibrillin-1 molecule in stabilising microfibrillar assemblies.

Actin Cytoskeleton↗
PubMed2003

The genome sequence of Caenorhabditis briggsae: a platform for comparative genomics.

The soil nematodes Caenorhabditis briggsae and Caenorhabditis elegans diverged from a common ancestor roughly 100 million years ago and yet are almost indistinguishable by eye. They have the same chromosome number and genome sizes, and they occupy the same ecological niche. To explore the basis for this striking conservation of structure and function, we have sequenced the C. briggsae genome to a high-quality draft stage and compared it to the finished C. elegans sequence. We predict approximately 19,500 protein-coding genes in the C. briggsae genome, roughly the same as in C. elegans. Of these, 12,200 have clear C. elegans orthologs, a further 6,500 have one or more clearly detectable C. elegans homologs, and approximately 800 C. briggsae genes have no detectable matches in C. elegans. Almost all of the noncoding RNAs (ncRNAs) known are shared between the two species. The two genomes exhibit extensive colinearity, and the rate of divergence appears to be higher in the chromosomal arms than in the centers. Operons, a distinctive feature of C. elegans, are highly conserved in C. briggsae, with the arrangement of genes being preserved in 96% of cases. The difference in size between the C. briggsae (estimated at approximately 104 Mbp) and C. elegans (100.3 Mbp) genomes is almost entirely due to repetitive sequence, which accounts for 22.4% of the C. briggsae genome in contrast to 16.5% of the C. elegans genome. Few, if any, repeat families are shared, suggesting that most were acquired after the two species diverged or are undergoing rapid evolution. Coclustering the C. elegans and C. briggsae proteins reveals 2,169 protein families of two or more members. Most of these are shared between the two species, but some appear to be expanding or contracting, and there seem to be as many as several hundred novel C. briggsae gene families. The C. briggsae draft sequence will greatly improve the annotation of the C. elegans genome. Based on similarity to C. briggsae, we found strong evidence for 1,300 new C. elegans genes. In addition, comparisons of the two genomes will help to understand the evolutionary forces that mold nematode genomes.

Animals↗
PubMed2003

Letter visibility and the viewing position effect in visual word recognition.

The ease with which printed words are recognized depends on the position at which the eyes initially fixate the word. In this study, we examined to what extent recognition performance for each fixation position depends on the average visibility of the word's constituent letters. Experiment 1 measured recognition performance to single letters embedded in strings of Xs (lengths of 5 and 7) for all combinations of letter position and initial fixation position in the string. In Experiment 2, recognition performance was measured for five-letter and seven-letter words as a function of initial fixation position in the word. Whereas average letter visibility showed a symmetric function in Experiment 1, the word recognition data of Experiment 2 showed the typical asymmetric curve. Combining the letter visibility data with measures of lexical constraint using absolute letter-in-string positions failed to capture the pattern in the word data. An alternative measure of constraint based on relative position coding of letters generated more accurate predictions.

Adult↗
PubMed2004

Mutations in the EGFR: the importance of genotyping.

Gefitinib reached the clinic with anticipation, but initial clinical trials were disappointing with only a small number of patients showing response to treatment. In two recent articles published simultaneously, Lynch et al., and Paez et al. help to explain those initial clinical findings. Both groups report that somatic mutations found within the coding region of the EGFR may predict the sensitivity to gefitinib treatment.

Antineoplastic Agents↗
PubMed1999

M1204, a novel 2',5' oligoadenylate synthetase with a ubiquitin-like extension, is induced during maturation of murine dendritic cells.

A novel molecule expressed by spleen dendritic cells (DC) was isolated using a subtractive hybridization approach. The full-length M1204 clone has 3063 bp, with 1415 bp spanning a single open reading frame, coding for a protein of a predicted size of about 50 kDa. This sequence has strong homology to 2', 5' oligoadenylate synthetase and contains a ubiquitin-like domain. In Northern blot analyses the mRNA is strongly expressed in spleen DC, whereas, in bone marrow-derived DC, the amount of mRNA increases during the maturation process. None of the other leukocytes nor several hemopoietic cell lines tested express this mRNA, but clear expression occurs in many organs, the highest levels being in thymus, lung, and bone marrow. In situ hybridization, combined with immunocytochemical staining of tissue sections of lung and spleen, shows colocalization of M1204 with the 2A1 and NLDC DC markers. In Western blot experiments, an antiserum raised against the recombinant M1204 recognizes a single band in bone marrow-derived DC and in the lung. The expressed oligoadenylate synthetase domain is active in synthesizing 2',5' diadenylate, which by itself may inhibit viral protein synthesis and may also function as a substrate for 2',5' oligoadenylate synthetase. Since the oligoadenylate/RNase L system provides early protection against virus infection, we hypothesize that M1204 prevents virus-induced cell death in DC.

2',5'-Oligoadenylate Synthetase↗
PubMed2003

Triage disposition of patients with acute myocardial infarction--ACSIS 2000.

BACKGROUND: In the emergency department the physician is often confronted with the decision of where to hospitalize a patient presenting with chest pain and a possible acute myocardial infarction--in the cardiac care unit or in the internal medicine ward. OBJECTIVE: To characterize the clinical factors involved in the triage disposition of patients hospitalized with AMI in Israel to either CCUs or IMWs and to determine to what extent the perceived probability of ischemia influenced the disposition decision. METHODS: During a 2 month nationwide prospective survey in the 26 CCUs and 82 of the 94 IMWs in Israel, we reviewed the charts of 1,648 patients with a discharge diagnosis of AMI. The probability of ischemia at admission was determined retrospectively by the Acute Coronary Ischemia Time-Insensitive Predictive Instrument. Co-morbidity was coded using the Index of Coexistent Diseases. RESULTS: The ACI-TIPI score for patients admitted to CCUs or to IMWs was 76.2% and 57.7% respectively (P < 0.001). Multivariate analysis showed that young patients with a high probability of ischemia and low co-morbidity or functional impairment were more likely to be hospitalized in CCUs than in IMWs. CONCLUSION: In Israel, the factors that strongly influence the initial triage disposition of AMI patients to CCUs or IMWs are age, perceived probability of ischemia, status of co-morbid conditions and functional impairment.

Age Distribution↗
PubMed2004

Length of hospital stay, diagnoses and pattern of investigation following emergency admission to an Irish teaching hospital.

Data on discharges from acute public hospitals in Ireland is recorded in the hospital in-patient enquiry (HIPE) system; its value in describing the casemix and pattern of resource utilization following emergency medical admissions has not been examined. We wished to determine whether there was a relationship between coded diseases at the time of discharge, patterns of investigation, and length of hospital stay (LOS) in a major teaching hospital. Data relating to emergency medical patients admitted to St James' Hospital Dublin between 1st January and 31st December 2002 was recorded. Of 5038 episodes evaluated, the median LOS was 6 days (IQR 3-13); this was significantly shorter when the patient was admitted under a general medical service (p<0.0001). There was also a positive correlation between patient age and LOS (r = 0.32; p<0.0001). No test request was associated with a shortened LOS. Prolonged LOS was associated with oesophago-gastro-duodenoscopy, echocardiography, computerised tomography, magnetic resonance imaging, and abdominal ultrasonography testing. Furthermore, prolonged LOS was associated with the following disease related groups (DRG) at discharge; codes related to heart failure, respiratory system, malignancy, stroke, diabetes, psychiatry, and anaemia. We found that clinical coding using the HIPE database strongly predicted hospital LOS for acute general medical admissions. Spare bed capacity is essential if an acute hospital is to operate efficiently and at a level of risk acceptable to patients. Therefore, determining major influences on hospital LOS is valuable, to develop potential strategies to optimise efficient utilization of acute bed capacity.

Adult↗
PubMed1991

The pma1 and pma2 H(+)-ATPases from Schizosaccharomyces pombe are functionally interchangeable.

The pma2 gene of Schizosaccharomyces pombe codes for a polypeptide having a predicted Mr of 110,126 and which is 79% identical to the plasma membrane H(+)-ATPase encoded by the pma1 gene. The pma2 gene, unlike pma1, is weakly expressed and not essential to mitotic growth. By constructing yeast strains in which the chromosomal pma2 gene is under control of the adh promoter, it has been possible to identify the overproduced ATPase in plasma membrane via formation of a phosphoenzyme. In a pma1-1 mutant strain whose ATPase activity is insensitive to vanadate, the overexpressed pma2 gene restores vanadate sensitivity. It also rescues a pma1 null mutant from lethality. These results demonstrate that the two H(+)-ATPases are functionally interchangeable in vivo but differently expressed.

Amino Acid Sequence↗
PubMed1985

Cloned mouse ribonucleotide reductase subunit M1 cDNA reveals amino acid sequence homology with Escherichia coli and herpesvirus ribonucleotide reductases.

We have isolated and sequenced overlapping cDNA clones containing the entire coding region of mouse ribonucleotide reductase subunit M1. The coding region comprises 2.4 kilobases and predicts a polypeptide of 792 amino acids (Mr 90,234) which shows striking homology with ribonucleotide reductases from Escherichia coli and the herpesviruses, Epstein-Barr virus and herpes simplex virus. The homologies reveal three domains: an N-terminal domain common to the mammalian and bacterial enzymes, a C-terminal domain common to the mammalian and viral ribonucleotide reductases, and a central domain common to all three. We speculate on the functional basis of this conservation.

Amino Acid Sequence↗
PubMed1989

Cloning, structure, and expression of the mitochondrial cytochrome P-450 sterol 26-hydroxylase, a bile acid biosynthetic enzyme.

The conversion of cholesterol into bile acids in the liver represents the major catabolic pathway for the removal of cholesterol from the body. In this complex biosynthetic pathway, at least 10 enzymes modify both the ring structure and side chain of cholesterol, resulting in the formation of the primary bile acids, cholic acid, and chenodeoxycholic acid. To gain insight into the details and regulation of this pathway, we have used protein sequencing and molecular cloning techniques to isolate and characterize a cDNA encoding the rabbit mitochondrial sterol 26-hydroxylase. This enzyme catalyzes the first step in the oxidation of the side chain of sterol intermediates in the biosynthesis of bile acids. The structure of the sterol 26-hydroxylase, as deduced by both DNA sequence analysis of the cDNA and protein sequence analysis, reveals it to be a mitochondrial cytochrome P-450. A signal sequence of 36 residues precedes a coding region of 499 amino acids, predicting a molecular weight of 56,657 for the mature protein. The identity of the 26-hydroxylase cDNA was further confirmed by expression in monkey COS cells employing a versatile eukaryotic expression vector. Blotting experiments revealed that the mRNA for this enzyme is expressed in many tissues and that it is encoded by a low copy number gene in the rabbit genome.

Amino Acid Sequence↗
PubMed1986

[Proteolytic events in the maturation of pro-neuropeptides. The somatostatin model].

The post-translational processing (maturation) of the precursors was studied on the model of the prosomatostatin. We have shown the presence of a single and common precursor to both somatostatin -28 and -14 in mouse hypothalamus, in contrast with the situation in the Teleostean fish, Lophius piscatorius. The search for a maturation activity was carried out using a synthetic undecapeptide substrate including in its sequence the cleavage site for somatostatin-14 release. Using this peptide, we characterized in rat brain cortex extracts a specific enzyme activity of 90 kD. This "maturase", colocalized in the neurosecretory granules with the somatostatin products, generates both the N-terminal peptide S-28, and the tetradecapeptide hormone (S-14) from the somatostatin-28, acting as a "S-28 convertase" producing free Arg and Lys residues present at the pair of basic amino acids signal. We propose a model where three peptide bonds are cleaved by this enzymatic activity. In the teleostean fish: Lophius piscatorius, two precursors coding for two different somatostatin were predicted by the determination of cDNA sequence. In this system, we observed the presence of a unique form of the tetradecapeptide hormone. We show that the final maturation product of the second precursor is a new 28 amino acid hormone called Somatostatin-28 II. Moreover, the product of this second gene after the action of the Somatostatin-28 convertase from rat brain cortex is the (Tyr7, Gly 10)S-14 derivative predicted by the clone.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Molecular cloning and nucleotide sequence analysis of rat PCNA/cyclin cDNA.

The 'proliferating cell nuclear antigen' (PCNA), also known as cyclin, accumulates in the nuclei of dividing and transformed cells and reacts with autoantibodies from certain lupus patients. A full-length cDNA (1195 bp) clone encoding PCNA/cyclin was isolated from rat thymocyte cDNA library. The nucleotide sequence reveals an open reading frame of 783 nucleotides coding for 28.7 kD protein. The predicted amino acid sequence and composition are in excellent agreement with the published protein data of rabbit PCNA. We report the entire nucleotide sequence of the cDNA and complete amino acid sequence for rat PCNA/cyclin.

Amino Acid Sequence↗
PubMed1988

Structure of the human neutrophil elastase gene.

The gene for human neutrophil elastase (NE), a powerful serine protease carried by blood neutrophils and capable of destroying most connective tissue proteins, was cloned from a genomic DNA library of a normal individual. The NE gene consists of 5 exons and 4 introns included in a single copy 4-kilobase segment of chromosome 11 at q14. The coding exons of the NE gene predict a primary translation product of 267 residues including a 29-residue N-terminal precursor peptide and a 20-residue C-terminal precursor peptide. Analysis of the N-terminal peptide sequence suggests it contains a 27-residue "pre" signal peptide followed by a "proN" dipeptide, similar to that of other blood cell lysosomal proteases. The sequences for the mature 218-residue NE protein are included in exons II-V. The 5'-flanking region of the gene includes typical TATA, CAAT, and GC sequences within 61 base pairs (bp) of the cap site. The sequence 1.5 kilobases 5' to exon I contains several interesting repetitive sequences including six tandem repeats of unique 52- or 53-bp sequences. The 5'-flanking region also contains a 19-bp segment with 90% homology to a segment of the 5'-flanking region of the human myeloperoxidase (MPO) gene, a gene also expressed in bone marrow precursor cells and a protein stored in the same neutrophil granules as NE. In addition, like the MPO gene, the NE 5'-flanking region has several regions with greater than or equal to 75% homology to sequences 5' to c-myc, but there is no overlap between the NE-c-myc and MPO-c-myc homologous sequences.

Amino Acid Sequence↗
PubMed1987

Bovine high molecular weight kininogen. The amino acid sequence, positions of carbohydrate chains and disulfide bridges in the heavy chain portion.

The existence of two types of circulating bovine plasma high molecular weight kininogen (HMWK) was predicted from analyses of complementary DNAs coding for this protein (Kitamura, N., Takagaki, Y., Furuto, S., Tanaka, T., Nawa, H., and Nakanishi, S. (1983) Nature 305, 545-549). The present protein-based study provided evidence in support of the proposed amino acid sequence derived from analysis of the cDNA clone, and the results confirm the existence of two types of circulating HMWK. Type I HMWK contains a heavy chain composed of 361 residues, while the heavy chain of type II HMWK contains 359 residues. The amino acid sequences of type I and type II HMWK determined in this study were identical to that inferred from the cDNA sequence with the exception of microheterogeneity observed in the cDNA at position 87 (Glu/Gln) and 168 (Lys/Arg). The heavy chain of type I HMWK contains 4 asparagine-linked carbohydrate chains at Asn-69, -150 (or -151), -179, and -186, while the heavy chain of type II HMWK contains these and an additional carbohydrate chain at Asn-264. In addition, a carbohydrate chain was found to be O-glycosidically linked to Thr-118 in both chains. Among nine disulfide linkages found in HMWK, eight intrachain disulfide pairs were established in the heavy chain. One interchain disulfide bridge occurs between the heavy chain and the light chain. This disulfide pairing, as well as repeating amino acid sequences observed in the heavy chain, provides strong evidence for the existence of three homologous domains in the heavy chain of bovine HMWK.

Amino Acid Sequence↗
PubMed1982

Assembly of the mitochondrial membrane system. Processing of the apocytochrome b precursor RNAs in Saccharomyces cerevisiae D273-10B.

The DNA sequence of the apocytochrome b gene in Saccharomyces cerevisiae D273-10B contains two intervening sequences (Nobrega, F. G., and Tzagoloff, A. (1980) J. Biol. Chem. 255, 9828-9837). The exon-intron boundaries of the gene have been determined in this study from the sequence of the DNA which was copied from the mRNA. A protein of 385 amino acid residues is predicted from the 1155-nucleotide long coding regions. Northern blot analysis of total mitochondrial RNA, probed with restriction fragments from both exon and intron regions of the gene, reveals a 4.3-kilobase (kb) transcript containing both introns and two partially spliced intermediates, one (2.9 kb) lacking the first intron and the other (3.6 kb) lacking the second intron. The most abundant transcript (2.1 kb) hybridizes only to exon probes and is presumed to the fully spliced mRNA. S1 nuclease mapping of the purified mRNA indicates existence of two separate RNAs with identical 3' termini but differing by approximately 217 nucleotides at their 5' ends. The larger transcript has a 950-nucleotide nontranslated leader. Analyses of the RNA species present in various rho- and mit- mutants indicate that: 1) exon mutants process both introns, albeit not as efficiently as wild type, 2) intron mutants blocked in the excision of the first or second intron are capable of processing the alternate intron, suggesting a non-obligatory order of excision of the two intervening sequences, and 3) excision of the second intron occurs in rho- mutants and therefore does not require a mitochondrial translation product.

Base Sequence↗
PubMed1997

The identification and significance of a Thr-->Pro polymorphism in kringle IV type 8 of apolipoprotein(a).

Elevated plasma levels of lipoprotein(a) [Lp(a)] represent a significant independent risk factor for the development of atherosclerosis. Interindividual levels of apo(a) vary over 1000-fold and are mainly due to inheritance that is linked to the locus of the apolipoprotein(a) [apo(a)] gene. The apo(a) gene encodes multiple repeats of a sequence exhibiting up to 85% DNA sequence homology with plasminogen kringle IV (K.IV), a lysine binding domain. In our search for sequence polymorphisms in the K.IV coding domain, we identified a polymorphism predicting a Thr-->Pro substitution located at amino acid position 12 of kringle IV type 8 of apo(a). The functional and clinical significance of this polymorphism was analysed in a case-control study and by comparing the in vitro lysine binding characteristics of the two Lp(a) subtypes. The case-control study (involving 153 subjects having symptomatic atherosclerosis and 153 age and gender matched normolipidemic controls) revealed a overall allele frequency for the Thr12-->Pro substitution in kringle IV type 8 of 14% and a negative association between presence of the Pro12-subtype and symptomatic atherosclerosis (p < 0.03). The in vitro lysine binding studies, using Lp(a) isolated from subjects homozygous for either Thr12 or Pro12 in K.IV type 8, revealed comparable lysine-Sepharose binding fractions for the two subtypes. The binding affinity (Kd) for immobilised plasmin degraded des-AA-fibrin (Desafib-X) was also comparable for the two subtypes, however a decreased maximal attainable binding (Bmax) for immobilised desafib-X was observed for the Pro12-subtype Lp(a).

Adult↗
PubMed2000

Homology-based gene structure prediction: simplified matching algorithm using a translated codon (tron) and improved accuracy by allowing for long gaps.

MOTIVATION: Locating protein-coding exons (CDSs) on a eukaryotic genomic DNA sequence is the initial and an essential step in predicting the functions of the genes embedded in that part of the genome. Accurate prediction of CDSs may be achieved by directly matching the DNA sequence with a known protein sequence or profile of a homologous family member(s). RESULTS: A new convention for encoding a DNA sequence into a series of 23 possible letters (translated codon or tron code) was devised to improve this type of analysis. Using this convention, a dynamic programming algorithm was developed to align a DNA sequence and a protein sequence or profile so that the spliced and translated sequence optimally matches the reference the same as the standard protein sequence alignment allowing for long gaps. The objective function also takes account of frameshift errors, coding potentials, and translational initiation, termination and splicing signals. This method was tested on Caenorhabditis elegans genes of known structures. The accuracy of prediction measured in terms of a correlation coefficient (CC) was about 95% at the nucleotide level for the 288 genes tested, and 97. 0% for the 170 genes whose product and closest homologue share more than 30% identical amino acids. We also propose a strategy to improve the accuracy of prediction for a set of paralogous genes by means of iterative gene prediction and reconstruction of the reference profile derived from the predicted sequences. AVAILABILITY: The source codes for the program 'aln' written in ANSI-C and the test data will be available via anonymous FTP at ftp.genome.ad.jp/pub/genomenet/saitama-cc. CONTACT: gotoh@cancer-c.pref.saitama.jp

Algorithms↗