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PubMed2004

Conservation of the genomic structure and receptor-mediated signaling between human and rat IL-24.

IL-24/MDA-7 is a new member of the IL-10 family of cytokines, which signals through two heterodimeric receptor complexes (IL-20R1/IL-20R2 and IL-22R/IL-20R2). Previously, we identified a rat gene named mob-5, which encodes a secreted protein that shares a high degree of homology with human IL-24. Expression of mob-5 and its putative cell surface receptors was shown to be upregulated by oncogenic ras. Here we show that not only do rat mob-5 and human IL-24 share a strikingly similar genomic structure but also that the rat MOB-5 protein can bind to and signal through the human IL-24 receptors. Like human IL-24, binding of the rat MOB-5 protein to the human IL-24 receptors leads to activation of the JAK/STAT pathway, which in turn supports receptor-dependent survival and proliferation of Ba/F3 cells. Furthermore, using human colon cancer cell lines with somatic knockout of either the mutant or the wild-type k-ras allele, we demonstrate that the human IL-24 receptors also are upregulated by oncogenic ras. Taken together, these results provide strong experimental evidence that MOB-5 is indeed the rat homolog of human IL-24.

Amino Acid Sequence↗
PubMed2004

The EIF2AK3 gene region and type I diabetes in subjects from South India.

Mutations in the EIF2AK3 gene underlie susceptibility to the Wolcott-Rallison syndrome, which is a monogenic disease associated with insulin-deficient neonatal diabetes. Furthermore, suggestive evidence of linkage between type 1 diabetes (T1DM) and the EIF2KA3 chromosomal region has been reported in Scandinavian families. We have investigated the hypothesis that polymorphic variants in and around the EIF2AK3 gene might partially account for susceptibility to T1DM in South Indian subjects. Excess transmission of the common alleles of two polymorphic markers (D2S1786 and 15INDEL, located within the gene) downstream of EIF2AK3, either singly (D2S1786, P = 0.01) and 15INDEL (P = 0.02) or as a combination (P < 0.001), were found in 234 families with a T1DM proband. There was also a clear paternal effect for the 15INDEL marker (P = 0.005) on disease susceptibility. The presence of the common allele of both markers was found in decreased frequency in the subjects with normal glucose tolerance compared to probands with T1DM (both P <or= 0.0001). Major common mutations of the EIF2AK3 gene in T1DM were excluded. In conclusion, this pilot study demonstrates an association between the region around the EIF2AK3 locus and T1DM susceptibility.

Adolescent↗
PubMed2005

Merging protein, gene and genomic data: the evolution of the MDR-ADH family.

Multiple members of the MDR-ADH (MDR: Medium-chain dehydrogenases/reductases; ADH: alcohol dehydrogenase) family are found in vertebrates, although the enzymes that belong to this family have also been isolated from bacteria, yeast, plant and animal sources. Initial understanding of the physiological roles and evolution of the family relied on biochemical studies, protein alignments and protein structure comparisons. Subsequently, studies at the genetic level yielded new information: the expression pattern, exon-intron distribution, in silico-derived protein sequences and murine knockout phenotypes. More recently, genomic and EST databases have revealed new family members and the chromosomal location and position in the cluster of both the first and new forms. The data now available provide a comprehensive scenario, from which a reliable picture of the evolutionary history of this family can be made.

Alcohol Dehydrogenase↗
PubMed2002

Recent developments in cartilage research: matrix biology of the collagen II/IX/XI heterofibril network.

Research on cartilage is intensifying as efforts expand to discover disease-modifying drugs to treat or prevent osteoarthritis. Proteolytic damage to the collagen fabric of cartilage is a critical, and probably early, component of the pathogenesis of degenerative joint disease. Here we summarize recent findings on the unique heteromeric structure of cartilage collagen fibrils, including the key role of collagen IX, a covalently bonded fibril-adapter molecule. A highly specific pattern of cross-linking sites that involves all three component gene products strongly suggests that collagen IX has evolved to function as an interfibrillar network-bonding agent. This is supported from the genetic evidence that mutations in all three collagen IX genes can produce a phenotype in which cartilage matrix integrity and early-onset osteoarthritis are a feature. From the structure of the cartilage collagen heteropolymer we also predict a pivotal role for telopeptide (non-triple-helical) proteolytic cleavages in the remodelling and degradation of collagen fibrils.

Animals↗
PubMed2003

Psp and Smgb: a model for developmental and functional regulation in the rat major salivary glands.

This paper summarizes past work detailing the developmental expression, cell and organ localization and biochemical features of the proteins parotid secretory protein (PSP) and isoforms of submandibular gland protein B (SMGB), and describes the molecular characterization of the genes that encode them, Psp and Smgb. These genes appear to be related to the BPI (bactericidal/permeability-increasing protein)/LBP (lipopolysaccharide-binding protein)/PLUNC (palate, lung and nasal epithelial clone) gene family found in the oral and respiratory organs of humans, rodents and cattle. We have emphasized the diverse patterns of expression of these genes among the submandibular, sublingual and parotid salivary glands of the rat, and their potential usefulness in defining and identifying genomic regulatory mechanisms of salivary development. While Psp is expressed similarly in the mouse, the putative Smgb gene of the mouse seems not to be expressed, apparently due to the insertion, between exons 1 and 2, of a gene for a retroviral protein.

Animals↗
PubMed2003

Cloning, characterization and chromosomal localization of the Sus scrofa SLC31A1 gene.

Copper is an essential element necessary for normal function of numerous enzymes in all living organisms. Uptake of copper into the cell is thought to occur through the membrane protein, SLC31A1 (CTR1), which has been described in a variety of species including yeast, human and mouse. In this study, we present cloning, gene structure, chromosomal localization and expression pattern of the Sus scrofa SLC31A1 gene, which encodes a 189 amino acid protein. The (SSC) SLC31A1 gene is organized in four exons and spans an approximately 2.3 kb genomic region. We have localized the gene to chromosome 1q28-q2.13 using a somatic cell hybrid panel. This region shows conservation of synteny with human chromosome 9, where the human SLC31A1 (CTR1) gene has been localized. Expression studies suggest that SLC31A1 mRNA is transcribed in all tissues examined.

Animals↗
PubMed1999

Renal basement membrane components.

Renal basement membrane components. Basement membranes are specialized extracellular matrices found throughout the body. They surround all epithelia, endothelia, peripheral nerves, muscle cells, and fat cells. They play particularly important roles in the kidney, as demonstrated by the fact that defects in renal basement membranes are associated with kidney malfunction. The major components of all basement membranes are laminin, collagen IV, entactin/nidogen, and sulfated proteoglycans. Each of these describes a family of related proteins that assemble with each other in the extracellular space to form the basement membrane. Over the last few years, new basement membrane components that are expressed in the kidney have been discovered. Here, the major components and their localization in mature and developing renal basement membranes are described. In addition, the phenotypes of basement membrane component gene mutations, both naturally occurring and experimental, are discussed, as is the aberrant deposition of basement membrane proteins in the extracellular matrix in several renal diseases.

Animals↗
PubMed2003

A 34 bp deletion within TSC2 is a rare polymorphism, not a pathogenic mutation.

Tuberous sclerosis (TSC) is an autosomal dominant hamartoma syndrome due to mutations in either TSC1 or TSC2. Previous reports have identified a mutation consisting of a 34 bp deletion affecting portions of exon 38 and the adjacent intron 38 of TSC2. We found this genetic variation in 4 of 800 TSC patients screened for mutations in TSC1 and TSC2. In every case, the variant was present in one unaffected parent of the sporadically affected TSC child. By RT-PCR analysis of RNA samples from two additional families with this genetic variant, we demonstrate that the allele with the deletion generates about 50% normal RNA transcript, and 50% RNA transcript including intron 38. In addition, there is no correlation between the extent of splicing and clinical status of family members. We also excluded the possibility of mosaicism in the parents with this variant. We conclude that this deletion is a rare polymorphism that does not cause TSC, but may be a modifier of the TSC phenotype.

Base Sequence↗
PubMed2005

Role of transcription factor KLF11 and its diabetes-associated gene variants in pancreatic beta cell function.

KLF11 (TIEG2) is a pancreas-enriched transcription factor that has elicited significant attention because of its role as negative regulator of exocrine cell growth in vitro and in vivo. However, its functional role in the endocrine pancreas remains to be established. Here, we report, for the first time, to our knowledge, the characterization of KLF11 as a glucose-inducible regulator of the insulin gene. A combination of random oligonucleotide binding, EMSA, luciferase reporter, and chromatin immunoprecipitation assays shows that KLF11 binds to the insulin promoter and regulates its activity in beta cells. Genetic analysis of the KLF11 gene revealed two rare variants (Ala347Ser and Thr220Met) that segregate with diabetes in families with early-onset type 2 diabetes, and significantly impair its transcriptional activity. In addition, analysis of 1,696 type 2 diabetes mellitus and 1,776 normoglycemic subjects show a frequent polymorphic Gln62Arg variant that significantly associates with type 2 diabetes mellitus in North European populations (OR = 1.29, P = 0.00033). Moreover, this variant alters the corepressor mSin3A-binding activity of KLF11, impairs the activation of the insulin promoter and shows lower levels of insulin expression in pancreatic beta cells. In addition, subjects carrying the Gln62Arg allele show decreased plasma insulin after an oral glucose challenge. Interestingly, all three nonsynonymous KLF11 variants show increased repression of the catalase 1 promoter, suggesting a role in free radical clearance that may render beta cells more sensitive to oxidative stress. Thus, both functional and genetic analyses reveal that KLF11 plays a role in the regulation of pancreatic beta cell physiology, and its variants may contribute to the development of diabetes.

Apoptosis Regulatory Proteins↗
PubMed2005

A missense mutation in the previously undescribed gene Tmhs underlies deafness in hurry-scurry (hscy) mice.

Mouse deafness mutations provide valuable models of human hearing disorders and entry points into molecular pathways important to the hearing process. A newly discovered mouse mutation named hurry-scurry (hscy) causes deafness and vestibular dysfunction. Scanning electron microscopy of cochleae from 8-day-old mutants revealed disorganized hair bundles, and by 50 days of age, many hair cells are missing. To positionally clone hscy, 1,160 F(2) mice were produced from an intercross of (C57BL/6-hscy x CAST/EiJ) F(1) hybrids, and the mutation was localized to a 182-kb region of chromosome 17. A missense mutation causing a critical cysteine to phenylalanine codon change was discovered in a previously undescribed gene within this candidate interval. The gene is predicted to encode an integral membrane protein with four transmembrane helices. A synthetic peptide designed from the predicted protein was used to produce specific polyclonal antibodies, and strong immunoreactivity was observed on hair bundles of both inner and outer hair cells in cochleae of newborn +/+ controls and +/hscy heterozygotes but was absent in hscy/hscy mutants. Accordingly, the gene was given the name "tetraspan membrane protein of hair cell stereocilia," symbol Tmhs. Two related proteins (>60% amino acid identity) are encoded by genes on mouse chromosomes 5 and 6 and, together with the Tmhs-encoded protein (TMHS), comprise a distinct tetraspan subfamily. Our localization of TMHS to the apical membrane of inner ear hair cells during the period of stereocilia formation suggests a function in hair bundle morphogenesis.

Animals↗
PubMed2005

BCL6b mediates the enhanced magnitude of the secondary response of memory CD8+ T lymphocytes.

A characteristic of the secondary response of CD8(+) T cells that distinguishes it from the primary response is the generation of greater numbers of effector cells. Because effector CD8(+) T cells are derived from a pool of less differentiated, replicating cells in secondary lymphoid organs, and because IL-2 mediates effector differentiation, the enhanced secondary response may reflect the enlargement of this generative pool by the transient repression of IL-2-mediated differentiation. We have examined for this function the transcriptional repressor BCL6b, a homologue of BCL6 that represses IL-2-induced B cell differentiation. BCL6b is expressed in a small subset of antigen-experienced CD8(+) T cells. Ectopic expression of BCL6b in CD8(+) T cells diminishes their growth in response to IL-2 in vitro. Female mice in which the BCL6b gene has been interrupted have normal primary responses of CD8(+) T cells to infection with vaccinia expressing the H-Y epitope, Uty, but Uty-specific, BCL6b(-/-), memory CD8(+) T cells have diminished recall proliferative responses to this epitope in vitro. BCL6b(-/-) mice also have normal primary CD8(+) T cell responses to influenza infection, but nucleoprotein peptide-specific, BCL6b(-/-), memory CD8(+) T cells have a cell autonomous defect in the number of effector cells generated in response to reinfection. Therefore, BCL6b is required for the enhanced magnitude of the secondary response of memory CD8(+) T cells.

Animals↗
PubMed2005

Lateral transfer of mating system in Stemphylium.

The fungal genus Stemphylium (Ascomycota) contains selfing species that evolved from outcrossing ancestors. To find out how selfing originated, we analyzed the Stemphylium MAT loci that regulate sexual reproduction in ascomycetes and compared MAT structures and phylogeny with a multigene Stemphylium species phylogeny. We found that some Stemphylium species' MAT loci contained a single gene, either MAT1-1 or MAT1-2, whereas others contained a unique fusion of the MAT1-1 and MAT1-2 regions. In all fused MAT regions, MAT1-1 was inverted and joined to a forward-oriented MAT1-2 region. As in the closely related Cochliobolus, Stemphylium species with fused MAT regions were able to self. Structural and phylogenetic analyses of the MAT loci showed that the selfing-conferring fused MAT regions were monophyletic with strong support. However, in an organismal phylogeny of Stemphylium species based on 106 isolates and four loci unrelated to mating, selfing arose in two clades, each time with strong support. Isolates with identical fused MAT regions were present in both clades. We showed that a one-time origin of the fused MAT loci, followed by a horizontal transfer across lineages, was compatible with the data. Another group of selfers in Stemphylium only had forward-oriented MAT1-1 at their MAT loci, constituting an additional and third origin of selfing in Stemphylium.

Ascomycota↗
PubMed2005

Disruption of the mouse inositol 1,3,4,5,6-pentakisphosphate 2-kinase gene, associated lethality, and tissue distribution of 2-kinase expression.

Many functions have been suggested for inositol 1,2,3,4,5,6-hexakisphosphate (InsP6), including mRNA export, nonhomologous end-joining, endocytosis, and ion channel regulation. However, it remains to be demonstrated that InsP6 is necessary for in vivo survival. We previously isolated a cDNA encoding the mammalian inositol 1,3,4,5,6-pentakisphosphate (InsP5) 2-kinase (2-kinase), the enzyme that converts InsP5 to InsP6. We used the sequence to search the BayGenomics databases and identify an ES cell line (XA232) that has a gene trap construct embedded in the 2-kinase gene. We obtained a mouse from this line, produced heterozygotes, and confirmed that the heterozygotes contain the trapping construct and have diminished 2-kinase activity. Breeding the XA232 heterozygotes produced no homozygous offspring; thus, loss of 2-kinase is lethal in mice. Dissections of embryonic day-8.5 uteri yielded no homozygous embryos; thus, the mice die before day 8.5 postcoitum. The gene trap construct contains a beta-galactosidase/neomycin reporter gene, allowing us to stain heterozygotes for beta-galactosidase to determine tissue-specific expression of 2-kinase protein. 2-kinase is expressed in the hippocampus, the cortex, the Purkinje layer of the cerebellum in the brain, in cardiomyocytes, and in the testes of adult mice. At day 9.5 postcoitum, 2-kinase was expressed in the notochord, the ventricular layer of the neural tube, and the myotome of the somites. Intense staining was also seen in the yolk sac, suggesting that InsP6 is necessary for yolk sac development or function. Furthermore, failure of yolk sac development or function is consistent with the early lethality of 2-kinase embryos.

Animals↗
PubMed2005

An unusual internal ribosome entry site in the herpes simplex virus thymidine kinase gene.

We have investigated a herpes simplex virus mutant that expresses low levels of thymidine kinase (TK), a phenotype associated with drug resistance and pathogenicity, despite a single-base deletion in the gene. Using a dual-reporter system, a 39-nt sequence including the mutation was shown to direct expression of the downstream reporter gene in reticulocyte lysate. Translation of the downstream reporter was not impaired when the mRNA lacked a 5' cap or had a stable stem loop 5' of the upstream reporter and was relatively resistant to edeine, an antibiotic that prevents AUG codon recognition by the 40S-eIF2-GTP/Met-tRNAi complex. Twelve nucleotides were as active as the original sequence for translation of the downstream reporter. Surprisingly, this sequence lacks an AUG codon. Analysis of point mutations showed that a CUG codon in the sequence was important. However, many single-base changes had only limited effects, and introduction of AUG codons did not increase translation. A mutant virus containing both the single-base deletion and a mutation that reduced downstream translation in vitro had significantly less TK activity than a virus with the single-base deletion alone. Thus, a remarkably short internal ribosome entry site (IRES) that lacks an AUG codon resides in the viral tk gene. The IRES appears to be responsible for TK expression from a drug-resistant mutant that would otherwise express no TK, which may contribute to pathogenicity. Because we found numerous short sequences with IRES activity, there might be many hitherto unrecognized polypeptides expressed at low levels from eukaryotic mRNAs.

Animals↗
PubMed2006

The wheat and barley vernalization gene VRN3 is an orthologue of FT.

Winter wheat and barley varieties require an extended exposure to low temperatures to accelerate flowering (vernalization), whereas spring varieties do not have this requirement. In this study, we show that in these species, the vernalization gene VRN3 is linked completely to a gene similar to Arabidopsis FLOWERING LOCUS T (FT). FT induction in the leaves results in a transmissible signal that promotes flowering. Transcript levels of the barley and wheat orthologues, designated as HvFT and TaFT, respectively, are significantly higher in plants homozygous for the dominant Vrn3 alleles (early flowering) than in plants homozygous for the recessive vrn3 alleles (late flowering). In wheat, the dominant Vrn3 allele is associated with the insertion of a retroelement in the TaFT promoter, whereas in barley, mutations in the HvFT first intron differentiate plants with dominant and recessive VRN3 alleles. Winter wheat plants transformed with the TaFT allele carrying the promoter retroelement insertion flowered significantly earlier than nontransgenic plants, supporting the identity between TaFT and VRN-B3. Statistical analyses of flowering times confirmed the presence of significant interactions between vernalization and FT allelic classes in both wheat and barley (P < 0.0001). These interactions were supported further by the observed up-regulation of HvFT transcript levels by vernalization in barley winter plants (P = 0.002). These results confirmed that the wheat and barley FT genes are responsible for natural allelic variation in vernalization requirement, providing additional sources of adaptive diversity to these economically important crops.

Adaptation, Physiological↗
PubMed2000

Interaction of the iron-sulfur cluster assembly protein IscU with the Hsc66/Hsc20 molecular chaperone system of Escherichia coli.

The iscU gene in bacteria is located in a gene cluster encoding proteins implicated in iron-sulfur cluster assembly and an hsc70-type (heat shock cognate) molecular chaperone system, iscSUA-hscBA. To investigate possible interactions between these systems, we have overproduced and purified the IscU protein from Escherichia coli and have studied its interactions with the hscA and hscB gene products Hsc66 and Hsc20. IscU and its iron-sulfur complex (IscU-Fe/S) stimulated the basal steady-state ATPase activity of Hsc66 weakly in the absence of Hsc20 but, in the presence of Hsc20, increased the ATPase activity up to 480-fold. Hsc20 also decreased the apparent K(m) for IscU stimulation of Hsc66 ATPase activity, and surface plasmon resonance studies revealed that Hsc20 enhances binding of IscU to Hsc66. Surface plasmon resonance and isothermal titration calorimetry further showed that IscU and Hsc20 form a complex, and Hsc20 may thereby aid in the targeting of IscU to Hsc66. These results establish a direct and specific role for the Hsc66/Hsc20 chaperone system in functioning with isc gene components for the assembly of iron-sulfur cluster proteins.

Adenosine Triphosphatases↗
PubMed2004

The 3'-untranslated region of the beta2-adrenergic receptor mRNA regulates receptor synthesis.

beta(2)-Adrenergic receptors (beta(2)-ARs) are low abundance integral membrane proteins that mediate the effects of catecholamines at the cell surface. Post-transcriptional regulation of beta(2)-AR is dependent, in part, on sequences within the 5'- and 3'-untranslated regions (UTRs) of the receptor mRNA. In this work, we demonstrate that 3'-UTR sequences regulate the translation of the receptor mRNA. Deletion of the 3'-UTR sequences resulted in 2-2.5-fold increases in receptor expression. The steadystate levels of beta(2)-AR mRNA did not change significantly in the presence or absence of the 3'-UTR, suggesting that the translation of the receptor mRNA is suppressed by 3'-UTR sequences. Introduction of the receptor 3'-UTR sequences into the 3'-UTR of a heterologous reporter gene (luciferase) resulted in a 70% decrease in reporter gene expression without significant changes in luciferase mRNA levels. Sucrose density gradient fractionation of cytoplasmic extracts from Chinese hamster ovary cells transfected with full-length receptor cDNA demonstrated that the receptor transcripts were distributed between polysomal and non-polysomal fractions. Deletion of 3'-UTR sequences from the receptor cDNA resulted in a clear shift in the distribution of receptor mRNA toward the polysomal fractions, favoring increased translation. The 3'-UTR sequences of the receptor mRNA were sufficient to shift the distribution of luciferase mRNA from predominantly polysomal fractions toward non-polysomal fractions in cells transfected with the chimeric luciferase construct. Taken together, our results provide the first evidence for translational control of beta(2)-AR expression by 3'-UTR sequences. Presumably, this occurs by affecting the receptor mRNA localization.

3' Untranslated Regions↗
PubMedDate not supplied

Lateral gene transfer in the deep sea of Mariana Trench: identification of nar gene cluster encoding membrane-bound nitrate reductase from Pseudomonas sp. strain MT-1.

The genes encoding membrane-bound nitrate reductase and its locus from Pseudomonas sp. strain MT-1, which is isolated from the sediment of Mariana Trench, were identified. To some extent, the gene organization in the cluster was different from those of other Pseudomonads. Quite interestingly, two genes encoding putative nitrate transporter (narK and narM) showed higher homologies to counterparts of organisms belonging to other genera than those of Pseudomonads. Especially, narM showed no significant homology to the genes for nitrate transporter of Pseudomonads, and was homologous to those of some marine bacteria. Further, arrangements of NarL- and Fnr-binding motifs in the cluster were different from those of P. stutzeri, closely related strain with MT-1. These observations clearly indicated that lateral transfer of genes in nar gene cluster had occurred in deep sea, and it may contribute to bacterial adaptation to environment of there.

Amino Acid Sequence↗