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Noriaki Shimokawa

Publications and source records attributed to Noriaki Shimokawa.

11 recordsLinked to original sources
PubMed2007

Alteration of cerebellar neurotropin messenger ribonucleic acids and the lack of thyroid hormone receptor augmentation by staggerer-type retinoic acid receptor-related orphan receptor-alpha mutation.

The mutant mouse staggerer (sg) harbors a deletion within the gene encoding the retinoic acid receptor-related orphan receptor-alpha (RORalpha). Homozygotes show aberrant cerebellar development. However, the mechanisms responsible for the cerebellar defect are still poorly understood. In the present study, the involvement of neurotropins (NTs), including nerve growth factor, brain-derived neurotropic factor, NT-3 and NT-4/5, and their receptors, which play a crucial role in brain development, on the cerebellar defects of sg mice was studied by semiquantitative RT-PCR and in situ hybridization histochemistry. An evident alteration of these mRNA levels was observed in both heterozygotes and homozygotes. Such difference was most evident in the internal granule cell layer. Because the changes in NT expression as well as morphological alterations in sg cerebellum are similar to those in hypothyroid animals, the effect of mutant RORalpha (RORsg) on transcriptional regulation through the thyroid hormone (TH) response element or the ROR response element (RORE) was then studied. RORsg neither activated the transcription through RORE nor suppressed RORalpha-induced transcription, indicating that it does not function as a dominant negative inhibitor. On the other hand, although wild-type RORalpha augmented TH receptor (TR)alpha1/beta1-mediated transcription through various TH response elements, RORsg was not effective in augmenting TR action. These results suggest that the cerebellar defect of the sg mouse is partly caused by the altered expression of NTs and the lack of augmentation of TR-mediated transcription by RORalpha as well as the absence of RORalpha action through RORE.

Animals↗
PubMed2005

The adrenal gland is a source of stress-induced circulating IL-18.

The present study compared plasma IL-18 levels between sham-operated and adrenalectomized mice following stress to investigate whether the adrenal gland contributes to the elevation of circulating IL-18 during stress. Two hours of stress provoked a robust, stressor-dependent, elevation of IL-18 mRNA and peptide in the adrenal gland in sham-operated mice. Consistently, levels of circulating mature IL-18 increased during stress and remained elevated for up to 6 h after stress. The stress-induced increase in circulating IL-18 was abolished by adrenalectomy. These findings demonstrate that the adrenal gland is required to achieve elevation of circulating IL-18 during stress.

Adrenal Glands↗
PubMed2005

Low dose hydroxylated PCB induces c-Jun expression in PC12 cells.

Polychlorinated biphenyls (PCBs) are known as environmental pollutants that may cause adverse health problems. Recently, accumulating evidence shows that PCBs express neurotoxicity through alteration of gene expression and signal transduction. On the other hand, c-Jun, a component of AP-1, is likely to coordinate transcription programs in response to various extracellular signals. However, little is known about the effects of PCBs on c-Jun expression. Here we investigated the expression of c-Jun in response to PCB. PC12 cells were incubated with hydroxylated PCB (4(OH)-2',3,3',4',5'-penta chlorobiphenyl, OH-PCB) at a final concentration from 10(-8) to 10(-5)M. The level of c-Jun expression was increased by OH-PCB at relatively low-dose; concentration of OH-PCB at 10(-8)M and 10(-7)M produced a 2.4- and 3.5-fold increase of c-Jun expression in respectively, compared with the values without OH-PCB treatment. Thyroid hormone (T3) did not induce such c-Jun expression, indicating that the effect of OH-PCB is not mediated through thyroid hormone signaling pathway. OH-PCB also enhanced phosphorylation of c-Jun NH2-terminal kinases. To determine whether the activation of Ca2+ channel is involved in the OH-PCB-induced c-Jun expression, we examined it using a L-type voltage-gated Ca2+ channel blocker nimodipine. Nimodipine partially inhibited OH-PCB-induced c-Jun expression by 50%. Moreover, Na+ channel antagonist tetrodotoxin inhibited OH-PCB-induced c-Jun expression completely. Taken together, our results indicate that exposure to OH-PCB induces c-Jun expression, and the response may be triggered by depolarization of a plasma membrane via Na+ influx, followed by Ca2+ influx partially through voltage-gated Ca2+ channels.

Animals↗
PubMed2005

Extracellular acidification enhances DNA binding activity of MafG-FosB heterodimer.

Cells are quite sensitive to a change of the extracellular pH and respond to it through detection of the H+/HCO3- level in extracellular fluid. However, little is known about molecular details induced by acidosis, such as intracellular pathways and gene expression. Here we describe properties of gene expression, protein interaction, and DNA binding activity of basic region leucine zipper (bZIP) transcription factor Maf and FosB during extracellular acidification. When cells were incubated with low pH medium, the expressions of small Maf proteins (MafG, MafK, and MafF) and FosB were clearly increased in an extracellular pH-dependent manner and expressed transiently with a peak after 1-2 h after stimulation. Immunofluorescence and protein binding studies indicated that MafG was partially co-localized with FosB in the nucleus and MafG can form heterodimers with FosB at extracellular pH 7.40. Moreover, we found that MafG-FosB complexes are able to bind to AP-1 consensus sequence, TGACTCA. To investigate whether extracellular acidification influences to dimerization and DNA binding activity of MafG and FosB, extracellular pH of cultured cells was decreased from 7.40 to 6.80. The decrease in extracellular pH led to enhanced dimerization of MafG with FosB leading to augmentation of the DNA binding activity of the heterodimer to AP-1 consensus sequence. Moreover, extracellular acidification induces mRNA expression of matrix metalloproteinase-1, one of the genes that are regulated by AP-1. These results suggest that MafG-FosB complexes are involved in transcriptional regulation in response to extracellular acidification.

Acids↗
PubMed2005

Polychlorinated biphenyl (PCB) alters acid-sensitivity of cultured neurons derived from the medulla oblongata.

Polychlorinated biphenyls (PCBs) are known as environmental pollutants that may cause adverse health problems. However, little is known about the effects of PCBs on acid-sensitive neurons of the medulla oblongata, which regulate respiration. Therefore, the present study was designed to examine whether PCB alters acid-sensitivity of cultured neurons derived from the rat medulla oblongata. When extracellular pH was shifted from 7.4 to 7.0, acid-sensitive neurons showed depolarization, which was measured by voltage-sensitive fluorescent dye. Exposure to PCB (Aroclor 1254) decreased the amplitude of depolarization in low pH and increased the resting membrane potential in a dose-dependent manner. Taken together, our results indicate that PCB potentially influences acid-sensitivity through alteration of the membrane potential of acid-sensitive neurons, which could affect the regulation of respiration.

Animals↗
PubMed2005

Molecular responses to acidosis of central chemosensitive neurons in brain.

Significant advances have been made in understanding how neurons sense and respond to acidosis at the cellular level. Decrease in pH of the cerebrospinal fluid followed by hypercapnia (increased arterial CO2) is monitored by the chemosensory neurons of the medulla oblongata. Then the intracellular signalling pathways are activated to regulate specific gene expression, which leads to a hyperventilatory response. However, little is known about molecular details of such cellular responses. Recent studies have identified several transcription factors such as c-Jun, Fos and small Maf proteins that may play critical roles in the brain adaptation to hypercapnia. Hypercapnic stimulation also activates c-Jun NH2-terminal kinase (JNK) cascade via influx of extracellular Ca2+ through voltage-gated Ca2+ channels. In addition, several transmembrane proteins including Rhombex-29 (rhombencephalic expression protein-29 kDa) and Past-A (proton-associated sugar transporter-A) have been implicated in regulation of H+ sensitivity and brain acidosis-mediated energy metabolism, respectively. This review discusses current knowledge on the signalling mechanisms and molecular basis of neuronal adaptation during acidosis.

Acidosis↗
PubMed2004

Recruitment of Pyk2 and Cbl to lipid rafts mediates signals important for actin reorganization in growing neurites.

Protein tyrosine kinase Pyk2 and multifunctional adaptor protein Cbl are implicated in the regulation of the cytoskeleton in several cell types. We report that Pyk2 and Cbl form a signaling complex that is translocated to lipid rafts and is enriched in growth cones of differentiating PC12 cells following growth factor stimulation. We found that Pyk2 and Cbl interacted with the adaptor protein ArgBP2, which also bound to flotillin-1, a component of lipid raft microdomains. These interactions contributed to recruitment of the Pyk2/Cbl complex to lipid raft compartments. In addition, Pyk2, Cbl and ArgBP2 were found co-localized with actin in axons and growth cones of differentiated PC12 cells. Moreover, co-expression of Pyk2, ArgBP2 and Cbl facilitated growth factor-induced formation of lamellipodia at the tip of neurites. Formation of these growth cone lamellipodia was dependent on intact lipid rafts and the Cbl-associated effectors Crk and phosphatidylinositol 3 (PI 3)-kinase. Our results indicate that recruitment of Pyk2/Cbl complexes to lipid rafts participates in growth factor-induced regulation of the actin cytoskeleton in growing neurites.

Actins↗
PubMed2004

Phosphorylation of JNK is involved in regulation of H(+)-induced c-Jun expression.

Cells respond to physical and chemical stimulations mediated by pH, osmolarity, and oxidative and mechanical stresses. Various signal transduction pathways cooperate and participate in these responses. Here we describe the role of c-Jun NH2-terminal kinase (JNK) in regulation of gene transcription after an increase in extracellular H+. When cells were incubated in low pH medium, the promotion of JNK phosphorylation and c-Jun expression was clearly observed in cells in an extracellular pH- and time-dependent manner. Activation of p38 and extracellular signal-regulated kinase 1/2 (ERK1/2) was extremely weak compared with that of JNK. An increase in extracellular H+ led to enhanced nuclear translocation of phosphorylated JNK leading to augmentation of the transcriptional activity of c-Jun. Nimodipine, a blocker of voltage-gated Ca2+ ion channels, prevented the phosphorylation of JNK and expression of c-Jun in a dose-dependent manner. These results suggest a novel intracellular signalling pathway for H+-induced c-Jun expression: an increase of extracellular H+ induces JNK phosphorylation and c-Jun expression via partly extracellular Ca2+ influx through voltage-gated Ca2+ channels.

Animals↗
PubMed2002

Past-A, a novel proton-associated sugar transporter, regulates glucose homeostasis in the brain.

The ventral medullary surface (VMS) of the medulla oblongata is known to be the site of the central chemosensitive neurons in mammals. These neurons sense excess H+/CO2 dissolved in the CSF and induce hyperventilation. To elucidate the mechanism of neuronal cell adaptation to changes of H+/CO2, we screened for hypercapnia-induced genes in the VMS. Here, we report cloning and characterization of a novel gene called proton-associated sugar transporter-A (Past-A), which is induced in the brain after hypercapnia and mediates glucose uptake along the pH gradient. Past-A comprises 751 amino acid residues containing 12 membrane-spanning helices, several conserved sugar transport motifs, three proline-rich regions, and leucine repeats. Past-A transcript was expressed predominantly in the brain. Moreover, the Past-A-immunoreactive neural cells were found in the VMS of the medulla oblongata, and the number of immunoreactive cells was increased by hypercapnic stimulation. Transient transfection of Past-A in COS-7 cells leads to the expression of a membrane-associated 82 kDa protein that possesses a glucose transport activity. The acidification of extracellular medium facilitated glucose uptake, whereas the addition of carbonyl cyanide m-chlorophenylhydrazone, a protonophore, inhibited glucose import. Together, our results indicate that Past-A is a brain-specific glucose transporter that may represent an adaptation mechanism regulating sugar homeostasis in neuronal cells after hypercapnia.

Administration, Inhalation↗
PubMed2002

Cbl-directed monoubiquitination of CIN85 is involved in regulation of ligand-induced degradation of EGF receptors.

Addition of ubiquitin or ubiquitin chains to target proteins leads to their mono- or polyubiquitination, respectively. Whereas polyubiquitination targets proteins for degradation, monoubiquitination is thought to regulate receptor internalization and endosomal sorting. Cbl proteins are major ubiquitin ligases that promote ligand-dependent polyubiquitination and degradation of receptor tyrosine kinases. They also recruit CIN85-endophilin in the complex with activated receptors, thus controlling receptor endocytosis. Here we show that the adaptor protein CIN85 and its homologue CMS are monoubiquitinated by Cbl/Cbl-b after epidermal growth factor (EGF) stimulation. Monoubiquitination of CIN85 required direct interactions between CIN85 and Cbl, the intact RING finger domain of Cbl and a ubiquitin acceptor site present in the carboxyl terminus of CIN85. Cbl-b and monoubiquitinated CIN85 are found in the complex with polyubiquitinated EGF receptors during prolonged EGF stimulation and are degraded together in the lysosome. Dominant interfering forms of CIN85, which have been shown previously to delay EGF receptor degradation, were also impaired in their monoubiquitination. Thus, our data demonstrate that Cbl/Cbl-b can mediate polyubiquitination of cargo as well as monoubiquitination of CIN85 to control endosomal sorting and degradation of receptor tyrosine kinases.

Adaptor Proteins, Signal Transducing↗