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Biomedical subjects

Y Yazaki

Publications and source records attributed to Y Yazaki.

At least 469 records · Page 26Linked to original sources
PubMed1995

Assignment of cardiac homeobox gene CSX to human chromosome 5q34.

Homeobox-containing genes play critical roles in regulating tissue-specific gene expression essential for tissue differentiation, as well as determining the temporal and spatial patterns of development. Recently, a human cardiac homeobox-containing gene, CSX, has been isolated. CSX is abundantly expressed in the human heart from fetal stages, suggesting that CSX plays an important role in human heart formation. In the present study, we have determined the chromosomal localization of CSX by fluorescence in situ hybridization techniques and systemic screening of a yeast artificial chromosome library using polymerase chain reaction. By these methods, CSX was mapped to 5q34 of human chromosome 5 near the boundary of 5q34 and 5q35. In this region, another homeobox-containing gene MSX2, which is expressed in various tissues including the conduction system of the developing heart, has been assigned. Localization of CSX and MSX2 to the same region of the human chromosome suggests that these genes may be coordinately regulated during human heart formation.

Animals↗
PubMed1995

Cloning of several species of MLL/MEN chimeric cDNAs in myeloid leukemia with t(11;19)(q23;p13.1) translocation.

The t(11;19)(q23;p13.1) translocation is thought to play an important role in pathogenesis of myeloid leukemias in older patients. The MLL gene involved in other 11q23 abnormalities was also rearranged by this translocation. Screening of cDNA libraries of the t(11;19)(q23;p13.1)-carrying leukemic cells resulted in the isolation of several species of fusion cDNAs between the MLL gene and an unknown gene on 19p13.1, named MEN (myeloid eleven-nineteen translocation), which is ubiquitously expressed. Although the MLL gene was alternatively spliced, the fusion protein should contain an N-terminal half of the MLL, including AT hook motifs, that is fused to the MEN protein with a lysine-rich sequence, suggesting that the MLL/MEN fusion protein could be a chimeric transcription factor. The MLL/MEN fusion transcripts of 8.0 kb were detected in leukemic cells of two cases with the translocation. The MLL/MEN fusion was consistent in all three cases of the t(11;19)(q23;p13.1)-carrying leukemia examined by RNA-based polymerase chain reaction. These findings strongly suggest that the t(11;19)(q23;p13.1) results in the fusion formation encoding a new class of potential chimeric transcription factor that contributes to leukemogenesis of myeloid lineage.

Acute Disease↗
PubMed1995

Erythropoietin induces tyrosine phosphorylation of the beta chain of the GM-CSF receptor.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) and erythropoietin (EPO) induce tyrosine phosphorylation of the GM-CSF receptor beta chain and the EPO receptor, respectively, although their receptors lack the tyrosine kinase activity. We have shown that EPO as well as GM-CSF induces tyrosine phosphorylation of the beta chain. Conversely, GM-CSF does not induce tyrosine phosphorylation of the EPO receptor. Tyrosine phosphorylation of the beta chain by stimulation with EPO is rapid and transient. EPO may trans-modulate a signaling pathway of GM-CSF by phosphorylating the beta chain of the GM-CSF receptor.

Amino Acid Sequence↗
PubMed1995

Identification of a 190-kDa protein as a novel substrate for the insulin receptor kinase functionally similar to insulin receptor substrate-1.

Recently, we generated mice with a targeted disruption of the insulin receptor substrate-1 (IRS-1) gene and demonstrated that they exhibited growth retardation and mild insulin resistance, suggesting the presence of IRS-1-independent pathway that partially substitutes for IRS-1 in IRS-1-deficient mice (Tamemoto, H., Kadowaki, T., Tobe, K., Yagi, T., Sakura, H., Hayakawa, T., Terauchi, Y., Ueki, K., Kaburagi, Y., Satoh, S., Sekihara, H., Yoshioka, S., Horikoshi, H., Furuta, Y., Ikawa, Y., Kasuga, M., Yazaki, Y., and Aizawa, S. (1994) Nature 372, 182-186). We have examined the insulin-stimulated tyrosine-phosphorylated proteins in livers of wild type and IRS-1-deficient mice. Tyrosine phosphorylation of an 190-kDa protein (pp190) by insulin was significantly stimulated in livers of IRS-1-deficient mice, which was weakly observed in wild type mice in addition to IRS-1. We also demonstrated that pp190 was immunologically distinct from IRS-1 and was associated with both the 85-kDa subunit of phosphatidylinositol 3-kinase and the Grb2/Ash molecule as IRS-1. We identified pp190 as a novel substrate for insulin receptor kinase (IRS-2), which can bind both PI3-kinase and Ash/Grb2, and whose tyrosine phosphorylation is specifically induced in IRS-1-deficient mice. These data suggested that pp190 may play some physiological roles in insulin's signal transduction; furthermore, induction of tyrosine phosphorylation of pp190 may be one of the compensatory mechanisms that substitute for IRS-1 in IRS-1-deficient mice.

Animals↗
PubMed1995

The molecular mechanism of the induction of the low density lipoprotein receptor by chenodeoxycholic acid in cultured human cells.

In a cultured human hepatoblastoma cell line, Hep G2, chenodeoxycholic acid (CDCA) induced LDL receptor mRNA levels approximately 4 fold and mRNA levels for HMG-CoA reductase and HMG-CoA synthase two fold. In contrast, the mRNA levels for mevalonate kinase, farnesyl pyrophosphate synthase and squalene synthase were not changed significantly. The pattern of the induction of the sterol-sensitive genes was similar to the induction by N-acetyl-leucyl-leucyl-norleucinal (ALLN), an SREBP degradation inhibitor, suggesting that CDCA may increase mature SREBPs. CDCA could inhibit the 25-hydroxycholesterol mediated inactivation of SREBP without affecting mRNA levels of SREBPs. These results suggest that CDCA can affect sterol metabolism by a novel mechanism involving the inhibition of the oxysterol-mediated inactivation of SREBP.

Alkyl and Aryl Transferases↗
PubMed1995

Role of macrophage colony-stimulating factor in the initial process of atherosclerosis.

The early atherosclerotic lesion is characterized by the presence of macrophage-derived foam cells. Macrophage colony-stimulating factor (M-CSF) specifically stimulates the functions of the monocyte-macrophages. To elucidate the role of M-CSF in the atherogenic process in vitro and in vivo, we studied the effects of M-CSF on enzyme activities of acidic cholesteryl ester (CE) hydrolase, neutral CE hydrolase, and acyl-coenzyme A:cholesterol acyltransferase (ACAT), and 300 micrograms of M-CSF was intravenously injected into WHHL rabbits aged 2.5 months for 8.5 months. M-CSF (100 ng/ml) enhanced acidic and neutral CE hydrolase, and ACAT activities by 3.2-fold, 4-fold, and 2.3-fold, respectively, in the presence of acetyl LDL, and M-CSF increased ratios of both acidic and neutral CE hydrolase activities to ACAT activity. After M-CSF injection into WHHL rabbits, we found very retarded progression of atherosclerosis. The accumulation of cholesterol ester was remarkably decreased in the aortae of M-CSF-treated animals (0.60 +/- 0.32 mg/g tissue), as compared to those of controls (4.21 +/- 0.65 mg/g tissue). The results suggest that M-CSF prevents the progression of atherosclerosis in WHHL rabbits by increasing net hydrolysis of cholesteryl ester in macrophages.

Animals↗
PubMed1995

An acute myeloid leukemia gene, AML1, regulates hemopoietic myeloid cell differentiation and transcriptional activation antagonistically by two alternative spliced forms.

The AML1 gene on chromosome 21 is disrupted in the (8;21)(q22;q22) and (3;21)(q26;q22) translocations associated with myelogenous leukemias and encodes a DNA binding protein. From the AML1 gene, two representative forms of proteins, AML1a and AML1b, are produced by alternative splicing. Both forms have a DNA binding domain but, unlike AML1b, AML1a lacks a putative transcriptional activation domain. Here we demonstrate that overexpressed AML1a totally suppresses granulocytic differentiation and stimulates cell proliferation in 32Dcl3 murine myeloid cells treated with granulocyte colony-stimulating factor. These effects of AML1a were canceled by the concomitant overexpression of AML1b. Such biological phenomena could be explained by our observations that (i) AML1a, which on its own has no effects as a transcriptional regulator, dominantly suppresses transcriptional activation by AML1b, and (ii) AML1a exhibits the higher affinity for DNA binding compared with AML1b. These antagonistic actions could be important in leukemogenesis and/or myeloid cell differentiation because more than half of myelogenous leukemia patients showed an increase in the relative amounts of AML1a.

Alternative Splicing↗
PubMed1995

Tec protein-tyrosine kinase is involved in interleukin-3 signaling pathway.

Among cytoplasmic protein-tyrosine kinases (PTKs) Tec now forms a novel subfamily with recently identified Tec-related PTKs (Btk and Itk/Tsk). Tec is known to be abundantly expressed in myeloid cells, and multiple forms of Tec protein can be generated via the mechanism of alternative splicing. In this report, we have investigated 5'-terminal diversity of the tec messages to demonstrate a predominant form of the Tec protein in mouse hematopoietic cell lines. Using anti-Tec serum, we could show that stimulation with interleukin-3 (IL-3) can induce tyrosine phosphorylation of Tec both in myeloid and pro-B-cell lines. IL-3 stimulation was also shown to induce kinase activity of Tec. Furthermore, we could demonstrate that Tec is constitutively associated with the Shc protein in vivo. Thus, we conclude that Tec is involved in the signaling pathway of IL-3.

Animals↗
PubMed1995

Matrix/integrin interaction activates the mitogen-activated protein kinase, p44erk-1 and p42erk-2.

Cell adhesion to extracellular matrix proteins is a dynamic process leading to dramatic changes in the cell phenotype. Integrins are one of the major receptor families that mediate cell-matrix contact. Evidence that integrins can act as signal transducing molecules has accumulated over the past few years. We report here that p44erk-1 and p42erk-2 mitogen-activated protein (MAP) kinases are rapidly phosphorylated on tyrosine residues upon adhesion of human skin fibroblasts to fibronectin or upon cross-linking of beta 1 integrins with antibody. The tyrosine phosphorylation of both kinases is associated with increased enzymatic activity. Pretreatment of the cells with cytochalasin D, which selectively disrupts the network of the actin filaments, completely inhibits this adhesion-mediated MAP kinase activation. Thus, our findings indicate that ligation of beta 1 integrins induces an increase in both tyrosine phosphorylation and enzymatic activity of p44erk-1 and p42erk-2 MAP kinases, and that the integrity of the actin cytoskeleton is essential in this process. Since MAP kinase behaves as a convergence point for diverse receptor-initiated signaling events at the plasma membrane, this serine/threonine kinase plays a key role and helps to account for the diversity of integrin-dependent cell functions.

Calcium-Calmodulin-Dependent Protein Kinases↗
PubMed1995

Increased tyrosine-phosphorylation of 55KDa proteins in beta-actin/Tec transgenic mice.

Protein-tyrosine kinases are considered to play important roles in cell proliferation and differentiation. Tec is a cytoplasmic protein-tyrosine kinase expressed in liver and hematopoietic tissues. To better understand Tec function in vivo, we generated transgenic mice expressing tec driven by the cytomegarovirus enhancer and beta-actin promoter. Among six transgenic lines generated, a particular line, named 2-11, expressed tec transgene product more widely and abundantly than the other lines. In the tissues of 2-11, the kinase activity of Tec was enhanced in accordance with the high expression of tec transgene product. Interestingly, tyrosine-phosphorylation of approximately 55KDa proteins in the tissues was induced. These results suggest that cellular proteins of 55KDa might be potential substrates of Tec in vivo.

Actins↗
PubMed1995

Characterization of three erythropoietin (Epo)-binding proteins in various human Epo-responsive cell lines and in cells transfected with human Epo-receptor cDNA.

Molecular cloning of a cDNA for a mouse erythropoietin (Epo) receptor (EpoR) has facilitated the understanding of the structure of this receptor. However, there is, as yet, no explanation for the discrepancy between the protein recognized by specific antibodies against mouse EpoR and the unexpectedly larger species that can be cross-linked to labeled Epo. It is unclear whether the product of an unidentified gene is included in the EpoR complex. In the present study, we directly compared the cross-linking patterns for human EpoR that were endogenously expressed in three types of Epo-responsive cell, and that was artificially expressed in nonhematopoietic cells after transfection with cDNA for human EpoR. We observed that 85-kD and 105-kD proteins formed ligand-receptor complexes in all the human Epo-responsive cells and, furthermore, that the formation of a complex derived from the 70-kD protein was dependent on the level of expression of the cloned EpoR mRNA in these cells. By contrast, a prominent cross-linked band derived from the 70-kD protein and a weaker band derived from the 80- to 85-kD protein, but no band derived from the 105-kD protein, could be shown in the case of nonhematopoietic cells transfected with the human EpoR cDNA. These observations suggest that the cloned cDNA for human EpoR alone does not allow generation of the complete EpoR in nonhematopoietic cells and that the 105-kD Epo-binding protein may represent the product of an as yet unidentified gene that is expressed in hematopoietic cells.

Amnion↗
PubMed1995

A subtype of diabetes mellitus associated with a mutation in the mitochondrial gene.

Recently, in patients with diabetes and deafness, researchers have identified an A to G transition at position 3243 in transfer ribonucleic acid(Leu)(UUR) [3243 base-pair (bp) mutation], originally found in patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes. To determine the prevalence of diabetic patients with this mutation in Japan, we screened selected cohorts of diabetic patients based upon type of diabetes, family history of diabetes, and age of onset; also screened were 550 unselected cohorts of diabetic patients, without prior information. We identified 5 patients with the 3243-bp mutation, suggesting that approximately 0.9% of diabetic patients have it. However, there were none with this mutation in 250 controls with normal glucose tolerance. We also studied the clinical characteristics and insulin secretory characteristics of diabetic patients with 3243-bp mutation. We propose that diabetes mellitus with 3243-bp mutation is a novel subtype of diabetes mellitus, maternally inherited diabetes, and deafness (MIDD).

Adult↗
PubMed1995

Growth stimulation of ferritin of human leukemia cells in vitro.

Ferritin has been reported to inhibit the growth of some leukemia cells in serum-supplemented culture. Recently we have found that ferritin stimulates the proliferation of human acute myeloblastic leukemia cells HL-60 and erythroleukemia cells K-562-T1 in serum-free medium. In this study, we examined the effect of ferritin against 14 human leukemia cell lines using human heart ferritin in serum-depleted culture medium. Among 14 cell lines tested, 10 were stimulated to proliferate by ferritin (maximum response at 30-300 ng/ml) with 0-1% fetal calf serum (FCS). The growth of all the cell lines was significantly inhibited by ferritin in the presence of 10% FCS. These results suggest that ferritin has dual functions; it promotes the growth of leukemia cells with low concentrations of FCS, but suppresses their growth with high concentrations of FCS.

Cell Division↗