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Y Yazaki

Publications and source records attributed to Y Yazaki.

At least 487 records · Page 27Linked to original sources
PubMed1995

HLA-linked susceptibility and resistance genes in Crohn's disease.

BACKGROUND & AIMS: Previous studies have shown a positive association of HLA-DR4-DQ4 with Crohn's disease in the Japanese population, but the association between Crohn's disease and HLA genes has yet to be fully elucidated. The aim of this study was to determine the Crohn's disease/HLA association using a DNA typing method. METHODS: A total of 90 unrelated patients with Crohn's disease and 336 healthy controls were typed for HLA class II genes including DP using DNA typing with the polymerase chain reaction-sequence-specific oligonucleotide probes method. RESULTS: Allelic analysis showed that DRB1*0405, DRB1*0410, DQA1*03, DQB1*0401, and DQB1*0402 are positively associated and DRB1*1501, DRB1*1302, and DQB1*0602 negatively associated with Crohn's disease. DP genes showed no significant association with Crohn's disease. Haplotype analysis showed positive associations with DRB1*0405-DQA1*03-DQB1*0401, DRB1*0410-DQA1*03-DQB1* 0402, and DRB1*0802-DQA1*03-BQB1-0402 haplotypes and negative associations with DRB1*1501-DQA1*0102-DQB1*0602 and DRB1*1302-DQA1*0102-DQB1*0604 haplotypes. CONCLUSIONS: In Crohn's disease in the Japanese population, the HLA-linked disease susceptibility gene is primarily associated with DQB1*04, in which leucine at the 56th position is a unique amino acid, and the disease resistance allele is suggested to be DQA1*0102.

Base Sequence↗
PubMed1995

Relationship between insulin-dependent diabetes mellitus (IDDM) and non-insulin-dependent diabetes mellitus: beta-cell function, islet cell antibody, and haptoglobin in parents of IDDM patients.

To examine the relationship between non-insulin-dependent diabetes mellitus (NIDDM) and insulin-dependent diabetes mellitus (IDDM), we studied beta-cell function, HLA type, and serologic markers of IDDM and NIDDM in the parents of IDDM patients. Fifty-two parents of 33 IDDM patients were examined in terms of islet-cell antibody (ICA) status, haptoglobin phenotype, HLA type, and insulin responses during an oral glucose tolerance test (OGTT). Twenty-seven parents were prospectively evaluated for up to 113 months. They were divided into the following three groups based on pattern of ICA positivity during the follow-up period: group 1, persistently positive ICA (n = 4); group 2, fluctuating ICA (n = 7); and group 3, persistently negative ICA (n = 16). Twenty-three percent (12 of 52) of the parents of IDDM patients had NIDDM, and 12% (six of 52) of the matched controls did. The prevalence of ICA in the parents (11 of 52, 21%) was greater than in normal controls (one of 112, P < .01). Diabetic parents tended to show a higher prevalence of ICA (six of 12, 50%) than nondiabetic parents (six of 40, 15%; P = .06). ICA-positive parents showed higher glucose levels and lower insulin responses than ICA-negative parents. Three of four parents in group 1 slowly progressed to an insulin-dependent state during 25 +/- 3 months of follow-up evaluation. Parents in group 2 and group 3 did not show any changes in glucose levels or insulin responses during the study.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Rabbit anti-chromatin antibodies recognize similar epitopes on a histone H1 molecule as lupus autoantibodies.

Autoantibodies in systemic lupus erythematosus (SLE) are believed to be produced through an antigen-driven mechanism, i.e., autosensitization with autoantigens. If this is the case, it is conceivable that antigenic determinants reactive with SLE autoantibodies and induced antibodies raised by immunization are quite similar. To examine this issue, rabbits were immunized with purified histone H1 or chromatin. Although immunization with purified histone H1 did not produce detectable amounts of anti-histone H1 antibodies, immunization with chromatin mounted relatively good antibody responses against not only all histone subunits but also ssDNA. Epitopes on a histone H1 molecule reactive with SLE autoantibodies and rabbit antisera were determined using deletion mutants of a histone H1 molecule. At least two epitopes reactive with induced antibodies were found on a histone H1 and these were closely related to or the same as major autoepitopes in SLE. These data might indicate that B cells producing anti-histone H1 autoantibodies are quite similar to those induced by immunization and provide additional evidence that autosensitization with an autoantigen might be operative and a particulate antigen chromatin could be one of the immunogens for the production of anti-nuclear antibodies of various kinds in SLE.

Animals↗
PubMed1995

Molecular mechanism of cardiac cellular hypertrophy by mechanical stress.

Mechanical stress is a major cause of cardiac hypertrophy. Although the mechanisms by which mechanical load induces cardiac cellular hypertrophy have long been a subject of great interest for cardiologists, the lack of a good in vitro system has hampered the understanding of the biochemical mechanisms. For these past several years, however, an in vitro cardiocyte culture system has made it possible to examine the biochemical basis for the signal transduction of mechanical stress. Passive stretch of cardiomyocytes cultured on silicone membranes activates protein kinase cascades of phosphorylation and induces an increase in protein synthesis and the expression of both immediate early genes such as c-fos, c-myc, c-jun, Egr-1, and late response genes such as beta-myosin heavy chain and skeletal alpha-actin. Although an important question regarding how mechanical stimulus is converted into biochemical signals remains unknown, the cultured cardiomyocyte is a good model to examine the signal transduction pathways of mechanical stress.

Actins↗
PubMed1995

Activation of Na(+)-H+ antiporter (NHE-1) gene expression during growth, hypertrophy and proliferation of the rabbit cardiovascular system.

The Na(+)-H+ antiporter is a unique transmembrane protein with multiple roles in cellular functions through intracellular alkalization. It participates in the regulation of intracellular pH, cell volume and intracellular signalling in response to various mitogenic stimuli. To clarify its role as a subcellular signal in cardiovascular remodeling like vascular hyperplasia or cardiac hypertrophy, we determined mRNA levels of the Na(+)-H+ antiporter isoform, NHE-1, in vascular smooth muscles and pressure-overloaded hearts in rabbits. The NHE-1 mRNA levels in rabbit aortas and hearts were developmentally regulated with high levels at embryonic and neonatal stages than in adults. In primary-cultured smooth muscle cells (SMC), the mRNA levels were increased during exponential growth, but decreased to initial levels at confluency. Growth of a mutant SMC line, C5, which is deficient in Na(+)-H+ antiporter activity, was markedly reduced in bicarbonate-free medium. However, when the activity was restored by transfecting cells with a full-length NHE-1 cDNA in an expression vector, the growth rate of C5 was accelerated again. After balloon injury to the vascular wall, the NHE-1 mRNA levels of the injured arteries were also increased, suggesting that Na(+)-H+ antiporter contributes to the network of the growth promoting systems in smooth muscle cells in vivo. Pressure-overload on the ventricle increased the NHE-1 mRNA levels in hearts approximately two-fold of sham-operated rabbits after 3 days and remained for at least two weeks (P < 0.05). We further demonstrated that 3-methylsulfonyl-4-piperidino-benzoyl guanidine mesylate (Hoe 694), a potent antagonist of Na(+)-H+ antiporter, partially inhibited stretch-induced activation of mitogen-activated kinase (MAP kinase) in the cultured cardiomyocytes. From these results, we conclude that activation of the Na(+)-H+ antiporter and its gene expression is involved in molecular mechanisms of both cardiac hypertrophy and vascular smooth muscle cell proliferation, indicating a potential target in developing new therapeutics for cardiovascular diseases.

Aging↗
PubMed1995

Immune response to hepatitis C virus core protein in mice.

To analyse the immune response to the hepatitis C virus (HCV) core protein, we immunized mice with the protein. BALB/c (H-2d) and C3H/He (H-2k) mice were high responders, while C57BL/6 (H-2b) mice were low responders in terms of Th cell proliferative responses. All the strains showed comparable levels of antibody responses to the HCV core protein. The Th cell lines recognized residues 61-90 of the HCV core protein in the context of I-Ad (BALB/c) and residues 11-30 in the context of I-Ek (C3H/He), respectively. The Th cell lines were restricted by I-Ab in C57BL/6 mice but recognized no synthetic peptide that spanned the region, although derivative clones from the line recognized residues 1-20 and 91-110 of the HCV core protein, respectively. The Th cell lines were Th 1 subset in all three strains based on the profile of lymphokine secretion. The major B cell epitope of the protein was found to be within residues 21-40 of the HCV core protein in all three strains. These observations should be useful for better understanding of the immune response to the HCV core protein in vivo.

Amino Acid Sequence↗
PubMed1995

Glomerular expression of smooth-muscle myosin heavy-chain isoforms in aminonucleoside nephrosis in rats.

1. We investigated the glomerular expression of three types of myosin heavy-chain isoforms, including S-myosin heavy-chain 40 (SM1), S-myosin heavy-chain 29 (SM2) and FS-myosin heavy-chain 34 (SMemb) in puromycin aminonucleoside nephrosis. 2. There was little change in SM1 and SM2 mRNA levels throughout the experiment. In contrast, glomerular SMemb mRNA increased on days 2 and 4 (before and soon after the onset of proteinuria, respectively), but declined on day 8 (the peak of proteinuria). 3. Histological myosin heavy-chain expression was examined using three antibodies against SM1, SM2 and SMemb. Immunohistochemically, SM1 and SM2 were absent in the glomeruli associated with puromycin aminonucleoside nephrosis until day 20. The SMemb isoform was barely detectable in normal glomeruli, but substantial amounts of SMemb were demonstrated in the glomeruli of rats with puromycin aminonucleoside nephrosis. In the puromycin aminonucleoside-treated rats, the number of SMemb-positive glomerular cells increased on days 2 and 4. 4. We examined whether levels of alpha-smooth-muscle actin or proliferating cell nuclear antigen correlated with myosin heavy-chain levels in the glomeruli of rats with puromycin aminonucleoside nephrosis. None of the cellular components in the glomeruli was positive for either alpha-smooth-muscle actin or proliferating cell nuclear antigen in puromycin aminonucleoside nephrosis. 5. Administration of methylprednisolone to puromycin aminonucleoside-treated rats resulted in the rapid disappearance of proteinuria. However, methylprednisolone did not affect SMemb mRNA or immunostaining in a glomeruli of rats with puromycin aminonucleoside nephrosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Protein kinase cascade activated by mechanical stress in cardiocytes: possible involvement of angiotensin II.

Mechanical stress induces cardiac hypertrophy and expression of specific genes in the cardiac myocytes. External stimuli are generally transduced into the nucleus through the activation of a protein kinase cascade. We have previously shown that stretching cardiomyocytes stimulates the activity of protein kinase C (PKC), mitogen-activated protein (MAP) kinase and S6 protein kinase. In the present study, we examined two other kinases, Raf-1 kinase and MAP kinase kinase, which are supposed to lie between PKC and MAP kinase in the protein kinase cascade. Stretching cardiocytes by using the in vitro system induced hyperphosphorylation of Raf-1 kinase and activation of MAP kinase kinase. The protein kinases activated by mechanical stress are similar to those activated by growth factors. We examined the possible involvement of angiotensin II (Ang II) in the protein synthesis and gene expression induced by mechanical stress. CV11974, an Ang II-receptor antagonist, partially suppressed the increases in amino acid incorporation, c-fos gene expression and MAP kinase activity induced by stretching. These results suggest that a variety of protein kinases are activated by mechanical stress and that locally produced Ang II may in part play important roles in converting mechanical stimuli into biochemical signals.

Angiotensin II↗
PubMed1995

A minimal and optimal cytotoxic T cell epitope within hepatitis C virus nucleoprotein.

Amino acid residues 81-100 of the hepatitis C virus (HCV) nucleoprotein contain a cytotoxic T cell epitope that is recognized by cytotoxic T lymphocytes (CTLs) in association with human leukocyte antigen B44. With panels of truncated and overlapping peptides, the minimal and optimal epitope recognized by CTLs was shown to be a 9-mer peptide (residues 88-96). The peptide can stimulate effectively CTLs that are able to recognize endogenously synthesized and processed HCV nucleoprotein.

Amino Acid Sequence↗
PubMed1995

Isolation of a cDNA for a growth factor of vascular endothelial cells from human lung cancer cells: its identity with insulin-like growth factor II.

We have found growth-promoting activity for vascular endothelial cells in the conditioned medium of a human lung cancer cell line, T3M-11. Purification and characterization of the growth-promoting activity have been carried out using ammonium sulfate precipitation and gel-exclusion chromatography. The activity migrated as a single peak just after ribonuclease. It did not bind to a heparin affinity column. These results suggest that the activity is not a heparin-binding growth factor (including fibroblast growth factors) or a vascular endothelial growth factor. To identify the molecule exhibiting the growth-promoting activity, a cDNA encoding the growth factor was isolated through functional expression cloning in COS-1 cells from a cDNA library prepared from T3M-11 cells. The nucleotide sequence encoded by the cDNA proved to be identical with that of insulin-like growth factor II.

Animals↗
PubMed1995

Tyrosine phosphorylation of the proto-oncogene product Vav and its association with the adapter Grb2/Ash in a human leukemia cell line UT-7.

The vav proto-oncogene product (Vav) is expressed exclusively in hematopoietic cells and is reported to have guanine nucleotide exchange activity. Here we report that granulocyte-macrophage colony-stimulating factor, interleukin-3, and erythropoietin induce tyrosine phosphorylation of Vav in a human leukemia cell line UT-7. Tyrosine phosphorylation of Vav is rapid and transient; it occurs within 1 min of the stimulation and at physiological concentrations of the factors. Furthermore, we show that Vav is constitutively associated with the adapter molecule Grb2/Ash in UT-7. These data suggest that tyrosine kinases, the adapter Grb2/Ash, and the guanine nucleotide exchange factor Vav are members of a signaling pathway leading to Ras activation in hematopoietic cells.

Adaptor Proteins, Signal Transducing↗
PubMed1995

c-Cbl is inducibly tyrosine-phosphorylated by epidermal growth factor stimulation in fibroblasts, and constitutively tyrosine-phosphorylated and associated with v-Src in v-src-transformed fibroblasts.

The c-cbl gene was cloned as the cellular homolog of the v-cbl oncogene that is the transforming component of a murine tumorigenic retrovirus, CAS NS-1, though the biological roles of c-Cbl remain to be elucidated. We have previously reported that c-Cbl is implicated in the signal transduction triggered by granulocyte-macrophage colony-stimulating factor or erythropoietin in hematopoietic cells. Here, we observed tyrosine phosphorylation of C-cbl in cells expressing epidermal growth factor receptor depending on EGF stimulation and in v-src transformed cells. Furthermore, c-Cbl was revealed to associate with v-Src in vivo. By means of binding experiments using glutathione S-transferase fusion proteins, we have found that the SH2 and SH3 domains of many proteins bind to c-Cbl. These findings strongly suggest that c-Cbl is implicated in a wide variety of signal transduction pathways, including those of EGF receptor and Src protein, as well as in the signaling pathways of hematopoietic cells.

3T3 Cells↗
PubMed1995

Growth inhibition of leukaemic cells carrying the t(3;21) by the AML1/EVI-1-specific antisense oligonucleotide.

The t(3;21)(q26;q22) translocation is thought to play an important role in the acute phase transformation of CML. The formation of the AML1/EVI-1 fusion gene by the translocation leads to expression of the AML1/EVI-1 fusion protein. Here we demonstrate that the AML1/EVI-1-specific antisense oligonucleotide markedly decreases the [3H]thymidine incorporation and growth of leukaemic cells carrying the t(3;21) and the t(9;22), but not those of K562 cells. These results indicate that the AML1/EVI-1 fusion protein could contribute to proliferation of the t(3;21)-carrying leukaemic cells after entering the blastic crisis phase of CML.

Base Sequence↗
PubMed1995

Dual functions of the AML1/Evi-1 chimeric protein in the mechanism of leukemogenesis in t(3;21) leukemias.

The chromosomal translocation t(3;21)(q26;q22), which is found in blastic crisis in chronic myelogenous leukemias and myelodysplastic syndrome-derived leukemias, produces AML1/Evi-1 chimeric transcription factor and is thought to play important roles in acute leukemic transformation of hemopoietic stem cells. We report here the functional analyses of AML1/Evi-1. It was revealed that AML1/Evi-1 itself does not alter the transactivation level through mouse polyomavirus enhancer-binding protein 2 (PEBP2; PEA2) sites (binding site of AML1) but dominantly suppresses the transactivation by intact AML1, which is assumed to be a stimulator of myeloid cell differentiation. DNA-binding competition is a putative mechanism of such dominant negative effects of AML1/Evi-1 because it binds to PEBP2 sites with higher affinity than AML1 does. Furthermore, AML1/Evi-1 stimulated c-fos promoter transactivation and increased AP-1 activity, as Evi-1 (which is not normally expressed in hemopoietic cells) did. Experiments using deletion mutants of AML1/Evi-1 showed that these two functions are mutually independent because the dominant negative effects on intact AML1 and the stimulation of AP-1 activity are dependent on the runt domain (DNA-binding domain of AML1) and the zinc finger domain near the C terminus, respectively. Furthermore, we showed that AML1/Evi-1 blocks granulocytic differentiation, otherwise induced by granulocyte colony-stimulating factor, of 32Dcl3 myeloid cells. It was also suggested that both AML1-derived and Evi-1-derived portions of the fusion protein play crucial roles in this differentiation block. We conclude that the leukemic cell transformation in t(3;21) leukemias is probably caused by these dual functions of AML1/Evi-1 chimeric protein.

3T3 Cells↗
PubMed1995

Of the GATA-binding proteins, only GATA-4 selectively regulates the human interleukin-5 gene promoter in interleukin-5-producing cells which express multiple GATA-binding proteins.

Interleukin-5 (IL-5) is produced by T lymphocytes and known to support B-cell growth and eosinophilic differentiation of the progenitor cells. Using ATL-16T cells which express IL-5 mRNA, we have identified a region within the human IL-5 gene promoter that regulates IL-5 gene transcription. This cis-acting sequence contains the core binding motif, (A/T)GATA(A/G), for GATA-binding family proteins and thus suggests the involvement of this family members. In this report, we describe the cloning of human GATA-4 (hGATA-4) and show that hGATA-4 selectively interacts with the -70 GATA site within the IL-5 proximal promoter region. By promoter deletion and mutation analyses, we established this region as a positive regulatory element. Cotransfection experiments revealed that both hGATA-4 and phorbol-12-myristate-13-acetate (PMA)-A23187 stimulation are necessary for IL-5 promoter activation. The requirement for another regulatory element called CLE0, which lies downstream of the -70 GATA site, was also demonstrated. ATL-16T cells express mRNAs of three GATA-binding proteins, hGATA-2, hGATA-3, and hGATA-4, and each of them has a potential to bind to the consensus (A/T)GATA(G/A) motif. However, using ATL-16T nuclear extract, we demonstrated that GATA-4 is the only GATA-binding protein that forms a specific DNA-protein complex with the -70 GATA site. An electrophoretic mobility shift assay with extracts of COS cells expressing GATA-binding proteins showed that GATA-4 has the highest binding affinity for the -70 GATA site among the three GATA-binding proteins. When the transactivation abilities were compared among the three, GATA-4 showed the highest activity. These results demonstrate the selective role of GATA-4 in the transcriptional regulation of the IL-5 gene in a circumstance where multiple members of the GATA-binding proteins are expressed.

Amino Acid Sequence↗
PubMed1995

Human GLUT-2 overexpression does not affect glucose-stimulated insulin secretion in MIN6 cells.

Accumulated evidence suggests that GLUT-2, in addition to its role in glucose transport, may also have other functions in glucose-stimulated insulin secretion. As a first step in addressing this possibility, we have engineered MIN6 cells overexpressing human GLUT-2 by transfection with human GLUT-2 cDNA. Stable transformants harboring human GLUT-2 cDNA exhibited an approximately twofold increase in 3-O-methyl-D-glucose uptake at 0.5 and 15 mM. Glucokinase activity or glucose utilization measured by conversion of [5-3H]glucose to [3H]H2O was not, however, altered in the MIN6 cells overexpressing human GLUT-2. Furthermore, glucose-stimulated insulin secretion was not affected by over-expression of human GLUT-2. An abundance of GLUT-2, therefore, does not correlate with the glucose responsiveness of cells in which glycolysis is regulated at the glucose phosphorylating step. These data suggest that GLUT-2 by itself does not have significant functions other than its role in glucose transport in glucose sensing by MIN6 cells.

3-O-Methylglucose↗
PubMed1995

Overexpression of human lipoprotein lipase protects diabetic transgenic mice from diabetic hypertriglyceridemia and hypercholesterolemia.

We investigated the role of the overexpression of lipoprotein lipase (LPL) in lipoprotein abnormalities in transgenic mice with streptozotocin-induced diabetes mellitus. Before the induction of diabetes, LPL activity was 4.6-fold in skeletal muscle and 2.0-fold higher in the heart in transgenic mice than in their nontransgenic littermates. LPL activity in skeletal muscles in diabetic nontransgenic mice and cardiac LPL activity in diabetic nontransgenic and transgenic mice were decreased. Body weights were similarly reduced, and no appreciable amount of adipose tissue was observed in diabetes in both groups. The plasma triglyceride level was lower in diabetic transgenic mice than in diabetic nontransgenic mice (33.2 +/- 22.5 versus 185.3 +/- 57.4 mg/dL). Induction of diabetes was associated with a significant increase in the plasma cholesterol level in nontransgenic mice (90.0 +/- 11.1 versus 163.9 +/- 39.3 mg/dL) but much less in transgenic mice. Our results indicate that overexpression of LPL in transgenic mice inhibited diabetes-associated hypertriglyceridemia and hypercholesterolemia but did not affect the loss of body weight induced by diabetes.

Animals↗