Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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The purpose of this study was to examine the sarcoplasmic reticulum (SR) Ca(2+)-uptake and the expression of phospholamban (PLB) and Ca(2+)-ATPase (CAA) in left ventricular (LV) and right ventricular (RV) myocardium of 6 normal (NL) dogs and 6 dogs with chronic heart failure (HF). In addition, gene expression of PLB and CAA was also examined in LV myocardium of NL and HF dogs. HF (LV ejection fraction 23+/-2%) was produced by multiple sequential intracoronary microembolizations. Oxalate-dependent Ca(2+)-uptake was measured in isolated membrane vesicles. Using specific dog myocardial monoclonal antibody, the expression of CAA, PLB and calsequestrin (CSQ) were measured in sodium dodecyl sulfate extract prepared from LV and RV tissue. Steady-state mRNA levels were determined by Northern hybridization using specific cDNA clones of PLB, CAA, CSQ, and glyceraldehyde-3-phosphate dehydrogenase (GADPH), a house keeping gene. SR Ca(2+)-uptake of NL and HF dogs increased with increasing Ca(2+)concentrations and reached a plateau at 3 microm in both LV and RV. Total capacity (134+/-9 v 224+/-10 nmol(45)Ca/mg protein/10 min, P<0.05) and maximal velocity (15+/-2 v 2 nmol(45)Ca/mg protein/min, P<0.05) of the SR to sequester Ca(2+)was significantly lower in LV myocardium of HF dogs compared to NL, whereas the Hill coefficient and the affinity of the Ca(2+)-pump for Ca(2+)were unchanged. LV tissue levels of the PLB and CAA, normalized to noncollagen protein or to CSQ and the PLB and CAA mRNA levels, normalized to CSQ or GADPH mRNA, were also significantly lower in HF dogs compared to NL. In RV myocardial tissue, no significant differences in total capacity of SR to sequester Ca(2+), maximal velocity of SR Ca(2+)-uptake, the affinity and Hill Coefficient of the Ca(2+)-pump for Ca(2+), or tissue levels of PLB and CAA were observed between NL dogs compared to HF dogs. We conclude that SR Ca(2+)-uptake and SR PLB and CAA protein and gene expression levels are reduced in LV myocardium of dogs with chronic HF. These abnormalities can lead to Ca(2+)-overload and subsequent global LV dysfunction.
J Mol Cell Cardiol 1999 Jul
PMID:Reduced sarcoplasmic reticulum Ca(2+)-uptake and expression of phospholamban in left ventricular myocardium of dogs with heart failure. 1040 55

The synthesis of the membrane-bound [NiFe]hydrogenase of Rhodobacter capsulatus (HupSL) is regulated negatively by the protein histidine kinase, HupT, and positively by the response regulator, HupR. It is demonstrated in this work that HupT and HupR are partners in a two-component signal transduction system. The binding of HupR protein to the hupS promoter regulatory region (phupS ) was studied using gel retardation and footprinting assays. HupR protected a 50 bp region localized upstream from the binding site of the histone-like integration host factor (IHF) regulator. HupR, which belongs to the NtrC subfamily, binds to an enhancer site (TTG-N5-CAA) localized at -162/-152 nt. However, the enhancer-binding HupR protein does not require the RpoN sigma factor for transcriptional activation, as is the case for NtrC from enteric bacteria, but functions with sigma70-RNA polymerase, as is the case for R. capsulatus NtrC. Besides, unlike NtrC from Escherichia coli, HupR activates transcription in the unphosphorylated form and becomes inactive by phosphorylation. This was demonstrated by replacing the putative phosphorylation site (D54) of the HupR protein with various amino acids or by deleting it using site-directed mutagenesis. Strains expressing mutated hupR genes showed high hydrogenase activities even in the absence of H2, indicating that hupSL transcription is activated by the binding of unphosphorylated HupR protein. Strains producing mutated HupRD54 proteins were derepressed for hupSL expression as were HupT- mutants. It is shown that the phosphorylated form of HupT was able to transfer phosphate to wild-type HupR protein but not to mutated D54 HupR proteins. Thus, it is concluded that HupT and HupR are the partners of a two-component regulatory system that regulates hupSL gene transcription.
Mol Microbiol 1999 Dec
PMID:The synthesis of Rhodobacter capsulatus HupSL hydrogenase is regulated by the two-component HupT/HupR system. 1059 24

The prevaleance of morbid obesity (body mass index of 35.0 or greater) is low in Japan (0.2-0.3%), and little systematic investigation of its cause in this population has been carried out. Leptin plays a central role in regulation of body weight; mice deficient in leptin develop marked obesity. We sought mutations in the leptin gene in 53 morbidly obese Japanese (maximum body mass index 35-60) including 46 with type 2 diabetes. Direct DNA sequencing was performed following polymerase chain reaction amplification. Apart from a silent mutation at codon 25 (CAA/CAG, glutamine) detected in eight subjects, no mutations were detected. We found a significantly higher prevalence of the variant leptin 25CAG allele among the 53 obese subjects (0.085) studied than in 132 nonobese control subjects (0.011, P<0.001). In Japanese populations mutations in the protein coding sequence of the leptin gene are unlikely to be a major cause of morbid obesity. However, the leptin 25CAG allele may be linked to morbid obesity in this population. Specifically, genetic variation located near the leptin gene may be involved in pathogenesis. The leptin polymorphism 25CAG appears to be a new genetic marker for obesity susceptibility, at least in Japanese.
J Mol Med (Berl) 2000
PMID:A polymorphic marker in the leptin gene associated with Japanese morbid obesity. 1114 Mar 77

Self-cleavage of the genomic and antigenomic ribozymes from hepatitis delta virus (HDV) requires divalent cation for optimal activity. Recently, the HDV genomic ribozyme has been shown to be active in NaCl in the absence of added divalent metal ion at low pH (apparent pKa 5.7). However, we find that the antigenomic ribozyme is 100 to 1000-fold less active under similar conditions. With deletion of a three-nucleotide sequence (C41-A42-A43) unique to the genomic ribozyme, the rate constant for cleavage decreased substantially, while activity of the antigenomic ribozyme was enhanced by introducing a CAA sequence. From the crystal structure, it has been proposed that C41 in this sequence is protonated. To investigate a possible connection between activity at low pH and protonation of C41, mutations were made that were predicted to either eliminate protonation or alter the nature of the tertiary interaction upon protonation. In the absence of added Mg2+, these mutations reduced activity and eliminated the observed pH-rate dependence. Thermal denaturation studies revealed a pH-sensitive structural feature in the genomic ribozyme, while unfolding of the mutant ribozymes was pH-independent. We propose that, in the absence of added Mg2+, protonation of C41 contributes to enhanced activity of the HDV genomic ribozyme at low pH.
J Mol Biol 2001 Feb 02
PMID:A pH-sensitive RNA tertiary interaction affects self-cleavage activity of the HDV ribozymes in the absence of added divalent metal ion. 1116 13

The partitioning locus (par) of plasmid pRA2 belongs to a recently discovered subgroup of plasmid partitioning systems that are evolutionarily distinct from the P1, F and R1/NR1 prototypes. The pRA2 par region was effective in stabilizing both pRA2 and F mini-replicons. Analysis of the nucleotide sequence revealed three potential coding regions that were designated parA, parB and parC. Through mutagenesis, parA and parB were found to be essential for partitioning function, whereas parC did not appear to be required. Using transcriptional reporter systems, it was demonstrated in vivo that ParB repressed par promoter activity by 60-fold and that ParA had little effect on transcriptional activity. Primer extension analysis revealed that the par transcriptional start point was located 47 nucleotides upstream of the parA translational start codon. Based on this information, putative -10 and -35 transcriptional signals were identified, and their subsequent deletion resulted in a dramatic reduction in promoter activity. The par promoter region was also demonstrated to exert incompatibility towards a plasmid with an active pRA2 par system. Nested deletions in this region allowed the incompatibility determinant, designated parS, to be localized. Recombinant ParA and ParB proteins were overexpressed and purified by affinity chromatography. Through in vitro binding experiments, purified ParB was shown to interact specifically with the par promoter region. DNase I footprinting revealed that ParB not only binds to the conserved sequence 5'-TCA AA(T/C) (G/C)CT CAA (A/T)A, which is present in three copies in the par promoter region, but also binds to the pRA2 partitioning site, parS. It appears that ParB has a dual role in pRA2 partitioning, being responsible for both the regulation of par transcription and the formation of a partition nucleoprotein complex at parS.
Mol Microbiol 2001 May
PMID:Molecular analysis of the pRA2 partitioning region: ParB autoregulates parAB transcription and forms a nucleoprotein complex with the plasmid partition site, parS. 1135 68

Polyglutamine repeats within proteins are common in eukaryotes and are associated with neurological diseases in humans. Many are encoded by tandem repeats of the codon CAG that are likely to mutate primarily by replication slippage. However, a recent study in the yeast Saccharomyces cerevisiae has indicated that many others are encoded by mixtures of CAG and CAA which are less likely to undergo slippage. Here we attempt to estimate the proportions of polyglutamine repeats encoded by slippage-prone structures in species currently the subject of genome sequencing projects. We find a general excess over random expectation of polyglutamine repeats encoded by tandem repeats of codons. We nevertheless find many repeats encoded by nontandem codon structures. Mammals and Drosophila display extreme opposite patterns. Drosophila contains many proteins with polyglutamine tracts but these are generally encoded by interrupted structures. These structures may have been selected to be resistant to slippage. In contrast, mammals (humans and mice) have a high proportion of proteins in which repeats are encoded by tandem codon structures. In humans, these include most of the triplet expansion disease genes.
J Mol Evol 2001 Mar
PMID:The comparative genomics of polyglutamine repeats: extreme differences in the codon organization of repeat-encoding regions between mammals and Drosophila. 1142 62

Spinocerebellar ataxia 2 (SCA2) is an autosomal dominant neurodegenerative disorder that results from the expansion of a cryptic CAG repeat within the exon 1 of the SCA2 gene. The CAG repeat in normal individuals varies in length from 14 to 31 repeats and is frequently interrupted by one or more CAA triplets, whereas the expanded alleles contain a pure uninterrupted stretch of 34 to 59 CAG repeats. We have previously reported the presence of a limited pool of 'ancestral' or 'at risk' haplotypes for the expanded SCA2 alleles in the Indian population. We now report the identification of two novel single nucleotide polymorphisms (SNPs) in exon 1 of the SCA2 gene and their characterization in 215 normal and 64 expanded chromosomes. The two biallelic SNPs distinguished two haplotypes, GT and CC, each of which formed a predominant haplotype associated with normal and expanded SCA2 alleles. All the expanded alleles segregated with CC haplotype, which otherwise was associated with only 29.3% of the normal chromosomes. CAA interspersion analysis revealed that majority of the normal alleles with CC haplotype were either pure or lacked the most proximal 5' CAA interruption. The repeat length variation at SCA2 locus also appeared to be polar with changes occurring mostly at the 5' end of the repeat. Our results demonstrate that CAA interruptions play an important role in conferring stability to SCA2 repeat and their absence predisposes alleles towards instability and pathological expansion. Our study also provides new haplotypes associated with SCA2 that should prove useful in further understanding the mutational history and mechanism of repeat instability at the SCA2 locus.
Hum Mol Genet 2001 Oct 01
PMID:CAG repeat instability at SCA2 locus: anchoring CAA interruptions and linked single nucleotide polymorphisms. 1168 90

Carcinogenic N-heterocyclic aromatic hydrocarbons are formed during the incomplete combustion of fossil fuels as well as cigarette smoke. N-Methyldibenzo[c,g]carbazole (NMeDBC) and 7H-dibenzo[c,g]carbazole (DBC) are members of this group. DBC induces mouse skin and liver tumors, whereas NMeDBC induces only mouse skin tumors. The objective of this study was to elucidate the mechanism of action of these compounds in skin by assessing the Ha-ras mutational spectra induced by a two-stage initiation-promotion protocol. NMeDBC (200 nmol) or DBC (200 nmol) was applied to the back skin of 24 female Hsd:ICR(Br) mice (12 per group) once. 12-O-tetradecanoylphorbol-13-acetate (TPA) (2 microg) was then applied twice weekly for 28 wk. Tumors were screened for Ha-ras mutations using enriched polymerase chain reaction and mutations defined by dideoxy sequencing. In DBC animals 58% produced papillomas, of which 71% had codon 61 mutations, 4% had codon 12 mutations, 4% had codon 13 mutations, and 21% had no Ha-ras mutations. In NMeDBC animals 92% produced papillomas, of which 73% had codon 61 mutations and 27% had no Ha-ras mutations. All of the codon 61 mutations, from both NMeDBC and DBC, were CAA-->CTA transversions. The DBC-induced tumors with the codon 12 mutation had a GGA-->GAA transition, and the codon 13 mutation was a GGC-->GTC transversion. These results suggest that NMeDBC is a more potent tumor inducer than DBC, but the resulting H-ras mutations in each group were predominantly in codon 61, and, therefore, mutation induction in skin by each chemical appears to proceed by a similar mechanism.
Mol Carcinog 2001 Oct
PMID:Comparison of Ha-ras mutational spectra of N-methyldibenzo[c,g]carbazole and 7H-dibenzo[c,g]carbazole-induced mouse skin tumors. 1174 17

The mitochondrial genome of Trypanosoma brucei does not encode tRNAs. Consequently, all mitochondrial tRNAs are imported from the cytosol and originate from nucleus-encoded genes. Analysis of all currently available T. brucei sequences revealed that its genome carries 50 tRNA genes representing 40 different isoacceptors. The identified set is expected to be nearly complete since all but four codons are accounted for. The number of tRNA genes in T. brucei is very low for a eukaryote and lower than those of many prokaryotes. Using quantitative Northern analysis we have determined the absolute abundance in the cell and the mitochondrion of a group of 15 tRNAs specific for 12 amino acids. Except for the initiator type tRNA(Met), which is cytosol specific, the cytosolic and the mitochondrial sets of tRNAs were qualitatively identical. However, the extent of mitochondrial localization was variable for the different tRNAs, ranging from 1 to 7.5% per cell. Finally, by using transgenic cell lines in combination with quantitative Northern analysis it was shown that import of tRNA(Leu)(CAA) is independent of its 5'-genomic context, suggesting that the in vivo import substrate corresponds to the mature, fully processed tRNA.
Mol Cell Biol 2002 Jun
PMID:tRNAs in Trypanosoma brucei: genomic organization, expression, and mitochondrial import. 1199 7

Schizophrenia is a major psychiatric disorder which is hypothesized to result from abnormal neurodevelopment or neural changes in adulthood and possibly associated with altered gene expression. To search for genes overexpressed in schizophrenia, cDNA library subtractive hybridization experiments between post-mortem human frontal cerebral cortices from schizophrenia individuals and neurological controls were carried out. One of the genes over-expressed in schizophrenia was identified as Nogo (also known as reticulon 4, RTN4, NI 250, or RTN-X), a myelin-associated protein which inhibits the outgrowth of neurites and nerve terminals. The elevated expression of Nogo mRNA in schizophrenia was confirmed by quantitative reverse transcription-polymerase chain reaction studies: 16.5 pg Nogo cDNA/microg total RNA in schizophrenia, and 10.2 pg Nogo cDNA/microg total RNA in controls (n=7; P=0.01, t-test for n<30). To identify possible polymorphisms in this gene, the Nogo nucleotide sequence was determined in a series of schizophrenia and control samples. The Nogo mRNA was found to contain a CAA insert polymorphism in the 3'-untranslated region. The prevalence of individuals homozygous for this CAA insert was significantly higher in schizophrenia compared to controls in genomic DNA samples extracted from post-mortem brain and blood samples: 17/81 or 21% in schizophrenia and 2/61 or 3% in controls (P=0.0022, chi(2)- and Fisher's exact-tests). Because the 3'-untranslated regions of eukaryotic genes are known to regulate gene expression, the increased frequency of the Nogo CAA insert in schizophrenia may contribute to abnormal regulation of Nogo gene expression, and may indicate a role for Nogo in disturbed neurodevelopment in schizophrenia.
Brain Res Mol Brain Res 2002 Nov 15
PMID:Schizophrenia and Nogo: elevated mRNA in cortex, and high prevalence of a homozygous CAA insert. 1242 46


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