Biomedical subjects

T Taniguchi

Publications and source records attributed to T Taniguchi.

At least 379 records · Page 21Linked to original sources

PubMed1996

Coupling of the IL2 receptor complex with non-receptor protein tyrosine kinases.

IL2 induces the proliferation of T lymphocytes through the IL2 receptor (IL2R) following T lymphocyte activation. The IL2R consists of at least three subunits, IL2R alpha, beta and gamma chains. The cytoplasmic regions of the IL2R beta and gamma chains are critical for transduction of the IL2 signal to the cell interior. Although IL2R beta and gamma chains lack an intrinsic protein tyrosine kinase (PTK) domain, these chains recruit various non-receptor type PTKs, such as p56lck (and other Src family PTKs), Jak PTKs and Syk PTKs. The recruited PTKs are then activated following ligand stimulation to invoke intracellular signalling for the cell proliferation. Furthermore, it has been demonstrated that the IL2R is linked to at least three distinct signalling pathways leading to the induction of the c-fos/c-jun genes, c-myc gene induction and bcl-2 gene induction. All these pathways are essential for IL2 mediated proliferative signalling and co-operate with each other to ensure a full scale signal transduction. These signalling pathways, except that for bcl-2 pathway, appear to be mediated by multiple PTKs: p56lck is critical for the induction of the c-fos/c-jun genes, the activation of Syk PTKs results in the induction of the c-myc gene and Jak3 PTK is required for the induction of both c-fos and c-myc genes. Finally, the IL2 system may serve as a prototype in understanding the pleiotropic function of cytokine receptors that lack intrinsic PTK domains; the cytoplasmic structures of these cytokine receptors have evolved to allow the combined action of different PTK family members (and other signalling molecules) expressed in different cell types, which may determine the activity of cytokines.

Humans↗

PubMed1996

Ocular hypotensive mechanism of intravitreally injected brain natriuretic peptide in rabbit.

PURPOSE: To determine whether brain natriuretic peptide (BNP) affects intraocular pressure (IOP), aqueous humor dynamics, and cyclic guanosine monophosphate (cGMP) concentration in the aqueous humor of the rabbit eye. METHODS: Twenty microliters of 10(-4) M and 10(-5) M (2 nmol, 0.2 nmol) BNP or atrial natriuretic peptide (ANP) were injected intravitreally into rabbit eyes, after which the IOP was measured using a pneumatonometer. Aqueous humor dynamics were studied at approximately 6 hours after the intravitreal injection of 2 nmol BNP. Aqueous humor flow was measured by fluorophotometry, and outflow facility was measured by the two-level constant pressure perfusion method, whereas uveoscleral outflow was measured by the fluorescein isothiocyanate-dextran perfusion method. The concentration of cGMP in the aqueous humor at 6 hours after injection of 2 or 0.2 nmol BNP also was measured by enzyme immunoassay. RESULTS: Intravitreal administration of BNP or of ANP caused a decrease in IOP, with a maximum effect at approximately 6 hours after the injection. Total outflow facility in eyes treated with 2 nmol BNP increased by 29%, although the aqueous humor flow and uveoscleral outflow did not show significant changes. The concentration of cGMP in the aqueous humor increased significantly in BNP-treated eyes. CONCLUSIONS: Intravitreal injection of BNP into rabbit eyes reduced IOP because of an increase in the outflow facility. Brain natriuretic peptide also increased the concentration of cGMP in the aqueous humor. It is probable that BNP-activated guanylate cyclase induced an upregulation of cGMP in the aqueous humor.

Animals↗

PubMed1996

[Behçet's disease].

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Behcet Syndrome↗

PubMed1996

Concentrations of vascular endothelial growth factor in the sera of normal controls and cancer patients.

Vascular endothelial growth factor (VEGF) is known to play crucial roles in tumor angiogenesis. We have investigated the circulating level of VEGF in sera from cancer patients as well as from healthy normal controls using a sensitive enzymatic immunoassay. Immunoreactive VEGF proteins were detectable in normal sera, and the cutoff level was determined to be 180 pg/ml. In examined patients with all types of cancer, including breast, gastrointestinal, hepatobiliary, and lung cancer, an aberrant increase in the circulating level of VEGF was detected. For example, in 137 primary breast cancer patients, 12 (8.8%) showed an aberrant increase in VEGF levels. This aberrant expression of VEGF in sera was significantly associated with the progression of the disease, and with VEGF protein expression in tumor tissues. In addition, a Western blot analysis confirmed the presence of the VEGF165 form in sera from a patient with recurrent breast cancer. It was concluded that VEGF was detectable in normal sera, and its level was increased in some populations of cancer patients. A positive angiogenesis regulator, VEGF might function as an endocrine growth factor, particularly for solid tumors.

Adult↗

PubMed1995

Identification of a member of the MAPKKK family as a potential mediator of TGF-beta signal transduction.

The mitogen-activated protein kinase (MAPK) pathway is a conserved eukaryotic signaling module that converts receptor signals into various outputs. MAPK is activated through phosphorylation by MAPK kinase (MAPKK), which is first activated by MAPKK kinase (MAPKKK). A genetic selection based on a MAPK pathway in yeast was used to identify a mouse protein kinase (TAK1) distinct from other members of the MAPKKK family. TAK1 was shown to participate in regulation of transcription by transforming growth factor-beta (TGF-beta). Furthermore, kinase activity of TAK1 was stimulated in response to TGF-beta and bone morphogenetic protein. These results suggest that TAK1 functions as a mediator in the signaling pathway of TGF-beta superfamily members.

Amino Acid Sequence↗

PubMed1995

Alterations of low molecular weight acid phosphatase protein level in Alzheimer's disease.

We have previously reported that the activity of low molecular weight (LMW) acid phosphatase, which can remove tyrosine-linked phosphates of epidermal growth factor receptor, was significantly decreased in Alzheimer brains. In the present study, a specific antibody was prepared to analyze the protein level of this enzyme. Western blot analysis indicated that the level of LMW acid phosphatase protein was significantly reduced, whereas the activity of LMW acid phosphatase per enzyme molecule was not changed in Alzheimer brains. These results suggest that the reduction of LMW acid phosphatase activity in Alzheimer brains is due to its decreased protein level in Alzheimer's disease.

Acid Phosphatase↗

PubMed1995

Neuroprotective effects of NBQX on hypoxia-induced neuronal damage in rat hippocampus.

Models of cerebral ischaemia were used for analysis of mechanism of neuronal cell death and/or damage. Ischaemia is caused dominantly by severe hypoxia and hypoglycaemia: in the present study, we examined the influence of severe in vivo hypoxia (5% O2/95% N2 for 30 min at 22 degrees C). After hypoxia, neuronal damage was observed in the CA3 and dentate gyrus (DG) after 3 and 21 days of survival, but not in the CA1.2,3-Dihydroxy-6-nitro-7-sulphamoyl-benzo(F)quinoxaline (NBQX), an antagonist for AMPA/kainate receptors, showed neuroprotective effects in the CA3 and DG. These results suggest that hypoxia may induce neuronal damage in the CA3 and DG through activation of AMPA/kainate receptors.

Analysis of Variance↗

PubMed1995

Activation of a cell-cycle-regulated histone gene by the oncogenic transcription factor IRF-2.

The human histone H4 gene FO108 is regulated during the cell cycle with a peak in transcription during early S phase. The cell-cycle element (CCE) required for H4 histone activation is a sequence of 11 base pairs that binds a protein factor in electrophoretic mobility shift assays that has been designated histone nuclear factor M (HiNF-M). Here we report the purification of HiNF-M, and show it to be a protein of relative molecular mass (M(r)) 48K that is identical to interferon (IFN) regulatory factor 2 (IRF-2), a negative transcriptional regulator of the IFN response. Recombinant IRF-2 (as well as the related protein IRF-1 (ref. 5)) binds the CCE specifically and activates transcription of this H4 histone gene. IRF-2 has been shown to have oncogenic potential, and our results demonstrate a link between IRF-2 and a gene that is functionally coupled to DNA replication and cell-cycle progression at the G1/S phase transition.

Animals↗

PubMed1995

The in vitro and in vivo resistance of synthetic enkephalin analogs to three enkephalin-hydrolyzing enzymes.

The magnitude of the in vitro and in vivo resistance of 3 synthetic enkephalin analogs, [D-Ala2,Met5]-enkephalin (DAME), [D-Ala2,Met5]-enkephalinamide (DAME-NH2) and [D-Ala2,D-Met5]enkephalin (DADME), to 3 enkephalin-hydrolyzing enzymes, amastatin-sensitive aminopeptidase (AsA), phosphoramidon-sensitive endopeptidase-24.11 (PsE) and captopril-sensitive dipeptidyl carboxypeptidase I (CsD), was estimated by comparing the potency of enkephalins in the absence of the peptidase inhibitor (PI) with that in the presence of the PI. The enhancement of the potency of enkephalins in the isolated mouse vas deferens preparation by 3 PIs, amastatin, phosphoramidon, and captopril, indicated that the resistance of enkephalins to AsA, PsE, or CsD was DADME [symbol: see text] DAME-NH2 [symbol: see text] DAME > [Met5]-enkephalin (ME), DADME > DAME-NH2 > DAME [symbol: see text] ME, or DADME [symbol: see text] DAME-NH2 > DAME > ME, respectively. Additionally, the data obtained by the s.c. administration of enkephalin analogs to 10-day-old rats with or without PI, showed that PsE played the most important role in the inactivation of both DAME and DAME-NH2. In addition to PsE, both AsA and CsD, or AsA alone, played the significant role in the inactivation of DAME, or DAME-NH2, respectively. In the inactivation of DADME, AsA alone played the significant role. These results showed that the 3 peptidases all played important roles in the inactivation of enkephalins, and therefore only an analog like DADME, which was quite resistant to the 3 enzymes, was able to produce the effect without PIs after its systemic administration. Since even DADME was not completely resistant to the 3 enzymes; however, its potency was further increased by pretreatment of infant rats with the PIs.

Aminopeptidases↗

PubMed1995

IL-2-induced gene expression of protein-tyrosine phosphatase LC-PTP requires acidic and serine-rich regions within IL-2 receptor beta chain.

A protein-tyrosine phosphatase LC-PTP is preferentially expressed in hematopoietic cells and is an early response gene in lymphokine stimulated cells. Here, we found the LC-PTP mRNA induction by IL-2 was markedly inhibited by several tyrosine kinase inhibitors. The induction required both the acidic and serine-rich regions of the IL-2 receptor beta chain (IL-2R beta) in mouse IL-3-dependent pro-B BAF-B03 transfectants. This is strikingly different from the induction of c-myc gene expression, which requires the serine-rich region alone. In addition, overexpression of activated-Lck or -Raf kinases resulted in augmented LC-PTP mRNA expression in myeloid cell line 32D transfectants. Considering the previous findings that the acidic region of the IL-2R beta is responsible for association with Lck and activation of Raf kinase, IL-2-induced expression of LC-PTP mRNA may be primarily transduced through a Lck-Raf mediated signaling pathway.

Animals↗

PubMed1995

Critical role of the interleukin 2 (IL-2) receptor gamma-chain-associated Jak3 in the IL-2-induced c-fos and c-myc, but not bcl-2, gene induction.

The interleukin 2 receptor (IL-2R) consists of three subunits, the IL-2R alpha, IL-2R beta c, and IL-2R gamma c chains. Two Janus family protein tyrosine kinases (PTKs), Jak1 and Jak3, were shown to associate with IL-2R beta c and IL-2R gamma c, respectively, and their PTK activities are increased after IL-2 stimulation. A Jak3 mutant with truncation of the C-terminal PTK domain lacks its intrinsic kinase activity but can still associate with IL-2R gamma c. In a hematopoietic cell line, F7, that responds to either IL-2 or IL-3, overexpression of this Jak3 mutant results in selective inhibition of the IL-2-induced activation of Jak1/Jak3 PTKs and of cell proliferation. Of the three target nuclear protooncogenes of the IL-2 signaling, c-fos and c-myc genes, but not the bcl-2 gene, were found to be impaired. On the other hand, overexpression of the dominant negative form of the IL-2R gamma c chain, which lacks most of its cytoplasmic domain, in F7 cells resulted in the inhibition of all three protooncogenes. These results provide a further molecular basis for the critical role of Jak3 in IL-2 signaling and also suggest a Jak PTK-independent signaling pathway(s) for the bcl-2 gene induction by IL-2R.

Animals↗

PubMed1995

IL-2 signaling involves recruitment and activation of multiple protein tyrosine kinases by the IL-2 receptor.

The IL-2 receptor (IL-2R) consists of three subunits, the IL-2R alpha, IL-2R beta, and IL-2R gamma chains, the last of which is also used in the receptors for IL-4, IL-7, IL-9, IL-13, and IL-15. The IL-2-induced proliferative signals emanate from the cytoplasmic domains of IL-2R beta and IL-2R gamma, but the nature and function of the signaling molecules that transmit these signals are not fully understood. Here we summarize our current understanding of the mechanisms by which IL-2R transmit signals by using multiple protein kinases. In fact, at least four protein tyrosine kinases (PTKs) are physically associated with IL-2R: p56lck (and its members), Syk PTK, and the Janus kinases, Jak1 and Jak3. cDNA expression studies revealed that the activation of these PTKs is critical for IL-2-induced proliferative signal transmission. Our findings indicate that a unique property of the IL-2R cytoplasmic domains is to recruit a variety of signaling molecules, which may suggest a mechanism by which these PTKs and other signaling molecules function in concert.

Animals↗

PubMed1995

An IRF-1-dependent pathway of DNA damage-induced apoptosis in mitogen-activated T lymphocytes.

Lymphocytes are particularly susceptible to DNA damage-induced apoptosis, a response which may serve as a form of 'altruistic suicide' to counter their intrinsic high potential for mutation and clonal expansion. The tumour suppressor p53 has been shown to regulate this type of apoptosis in thymocytes, but an as yet unknown, p53-independent pathway(s) appears to mediate the same event in mitogen-activated mature T lymphocytes. Here we show DNA damage-induced apoptosis in these T lymphocytes is dependent on the antioncogenic transcription factor interferon regulatory factor (IRF)-1. Thus two different anti-onco-genic transcription factors, p53 and IRF-1, are required for distinct apoptotic pathways in T lymphocytes. We also show that mitogen induction of the interleukin-1 beta converting enzyme (ICE) gene, a mammalian homologue of the Caenorhabditis elegans cell death gene ced-3, is IRF-1-dependent. Ectopic overexpression of IRF-1 results in the activation of the endogenous gene for ICE and enhances the sensitivity of cells to radiation-induced apoptosis.

Animals↗

PubMed1995

Altered specificity of IGF2 promoter imprinting during fetal development and onset of Wilms tumour.

The specificity of IGF2 promoter imprinting was examined in embryonal tissues and Wilms tumour. In several fetal tissues of approximately 12 weeks gestation, IGF2 was found to be monoallelically expressed from all IGF2 promoters i.e. P1, P2, P3 and P4. However, in tissues of slightly older gestation age (15-17 weeks) relaxation of imprinting at the P1 promoter was evident, although the P2-P4 promoters remained imprinted. These data indicate that early in embryogenesis a population of cells exists in which all IGF2 promoters are imprinted, but that as development proceeds the imprinting of the P1 promoter is relaxed. The pattern of IGF2 promoter imprinting was also analysed in Wilms tumour. In some tumours, the pattern of promoter imprinting was identical to that found in early fetal kidney, indicating that this tumour originates within early embryonic kidney tissue. In contrast, in tumours in which relaxation of imprinting had occurred, imprinting relaxation affected all IGF2 promoters. This aberrant pattern of promoter imprinting, which was not detected in fetal kidney, provides further evidence that pathological relaxation of IGF2 imprinting is involved in the genesis of Wilms tumour.

Adult↗

PubMed1995

Identification of two highly homologous presynaptic proteins distinctly localized at the dendritic and somatic synapses.

Through screening of a murine brain cDNA library, we have isolated two brain specific cDNAs encoding highly homologous proteins, named 921-L and 921-S, comprised of 134 amino acids with 80% identity. Immunohistological study with the mAbs raised against the bacterially expressed 921 proteins showed that 921-L protein is distributed at the dendritic region and 921-S at the neuronal somatic surface. Immuno-electron microscopic study revealed that both 921 proteins are localized at the presynaptic terminal, indicating that the 921 proteins are differentially expressed at the dendritic and somatic presynapses.

Adaptor Proteins, Vesicular Transport↗

PubMed1995

Molecular cloning of LSIRF, a lymphoid-specific member of the interferon regulatory factor family that binds the interferon-stimulated response element (ISRE).

Interferon regulatory factor (IRF) genes encode a family of DNA-binding proteins that are involved in the transcriptional regulation of type-I interferon and/or interferon-inducible genes. We report here the characterization of LSIRF, a new member of the IRF gene family cloned from mouse spleen by the polymerase chain reaction using degenerate primers. LSIRF was found to encode a 51 kDa protein that shares a high degree of amino acid sequence homology in the DNA-binding domain with other IRF family members. LSIRF expression was detectable only in lymphoid cells. In contrast to other IRF genes, LSIRF expression was not induced by interferons, but rather by antigen-receptor mediated stimuli such as plant lectins, CD3 or IgM crosslinking. In in vitro DNA binding studies, LSIRF was able to bind to the interferon-stimulated response element (ISRE) of the MHC class I promoter. The expression pattern and DNA binding activities suggest that LSIRF plays a role in ISRE-targeted signal transduction mechanisms specific to lymphoid cells.

Amino Acid Sequence↗

PubMed1995

Expression of platelet-derived endothelial cell growth factor/thymidine phosphorylase in human breast cancer.

We have investigated the expression of platelet-derived endothelial-cell growth factor/thymidine phosphorylase (PD-ECGF/dThdPase) in human breast-cancer tissues by the immunocytochemical method using anti-PD-ECGF/dThdPase monoclonal antibody. Out of 100 invasive-ductal-carcinoma tissue samples, 39 (39%) were evaluated as PD-ECGF/dThdPase-positive. The expression of PD-ECGF/dThdPase was identified mainly in the cytoplasma of tumor cells. The expression of PD-ECGF/dThdPase was significantly associated with the microvessel density assessed by immunostaining to factor-VIII-related-antigen (p < 0.05). However, there was no correlation between expression of PD-ECGF/dThdPase and menopausal status, tumor size, axillary lymph-node metastases, hormone-receptor status, epidermal-growth-factor receptor, or erb-B-2-protein and p53-protein expression. We suggest that expression of PD-ECGF/dThdPase plays an important role in the promotion of angiogenesis in human breast cancer.

Antibodies, Monoclonal↗

PubMed1995

Three distinct IL-2 signaling pathways mediated by bcl-2, c-myc, and lck cooperate in hematopoietic cell proliferation.

Two interleukin-2 receptor-dependent signaling pathways have thus far been identified: the c-fos/c-jun induction pathway mediated by src family protein-tyrosine kinases and the c-myc induction pathway. Here, we provide evidence for the existence of a third, rapamycin-sensitive pathway, which results in the induction of another proto-oncogene, bcl-2. In the hematopoietic cell line BAF-B03, the expression of any two of lckF505 (an active form of p56lck), Bcl-2, or c-Myc is sufficient to promote transit of the cell cycle, regardless of the activation state of the third pathway. We also provide evidence that epidermal growth factor receptor signaling may act through the same pathway that involves p56lck. These studies demonstrate a novel approach to dissecting signaling pathways regulating cellular proliferation.

Animals↗