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T Kuno

Publications and source records attributed to T Kuno.

At least 37 records · Page 2Linked to original sources
PubMed1999

The MAPK kinase Pek1 acts as a phosphorylation-dependent molecular switch.

The mitogen-activated protein kinase (MAPK) pathway is a highly conserved eukaryotic signalling cascade that converts extracellular signals into various outputs, such as cell growth and differentiation. MAPK is phosphorylated and activated by a specific MAPK kinase (MAPKK): MAPKK is therefore considered to be an activating regulator of MAPK. Pmk1 is a MAPK that regulates cell integrity and which, with calcineurin phosphatase, antagonizes chloride homeostasis in fission yeast. We have now identified Pek1, a MAPKK for Pmk1 MAPK. We show here that Pek1, in its unphosphorylated form, acts as a potent negative regulator of Pmk1 MAPK signalling. Mkh1, an upstream MAPKK kinase (MAPKKK), converts Pek1 from being an inhibitor to an activator. Our results indicate that Pek1 has a dual stimulatory and inhibitory function which depends on its phosphorylation state. This switch-like mechanism could contribute to the all-or-none physiological response mediated by the MAPK signalling pathway.

Amino Acid Sequence↗
PubMed1999

Bilateral Nonpalpable Breast Carcinomas in a Patient with BRCA2 Germ Line Mutation and Past History of Osteosarcoma.

A 34-year-old premenopausal woman developed asynchronous bilateral nonpalpable breast cancers at the age of 32 and 34 years. She had undergone amputation of her left lower leg because of osteosarcoma at the age of 16. Her mother had beendiagnosed with breast cancer at the age of 45. The clinicopathological features of the two breast tumors in this patient closely resembled each other; both were nonpalpable, and detectable only by helical CT scan. Histologically, they consisted mainly of an intraductal component with small grade 3 invasive foci. In addition, both tumors estrogen receptor (ER) status was negative, and both were positive for c-erbB-2 protein on immunohistochemical staining. A missense germ line mutation of BRCA2 (exon 25 codon 3118; Met3118Thr) was detected in this patient. These data may provide useful information on the carcinogenesis and biological behavior of breast cancers which develop in patients with BRCA2 germ line mutations.

Journal Article↗
PubMed1999

Diffuse cutaneous mastocytosis responding to cyproheptadine.

A 3-month-old male infant was referred to our department with a generalized brown, thickened leathery skin and blisters which had been present since birth; the blisters developed recurrently at sites of minor trauma, healing without scar formation, although Darier's sign was positive. Microscopically, biopsy specimens showed a dense dermal band-like infiltrate with mast cells, whereas a biopsy from a vesicle showed subepidermal bulla formation. Physical examination did not reveal any systemic involvement with mastocytosis and the patient was treated with cyproheptadine, which has considerable anti-serotonin activity and, interestingly, reduced the degree of blistering; this treatment might therefore be tried in other cases.

Cyproheptadine↗
PubMed1999

Dietary prevention of azoxymethane-induced colon carcinogenesis with rice-germ in F344 rats.

The modifying effect of dietary administration of defatted rice-germ and gamma-aminobutyric acid (GABA)-enriched defatted rice-germ on azoxymethane (AOM)-induced colon carcinogenesis was investigated in two experiments with male F344 rats. In the first experiment (the pilot study), the effects of the defatted rice-germ, the GABA-enriched defatted rice-germ and rice-germ on AOM-induced (15 mg/kg body wt once a week for 3 weeks) formation of aberrant crypt foci (ACF) were examined. The latter two preparations (2.5% in the diet) significantly inhibited ACF formation (P < 0.005). In the second experiment, a long-term study of the effects of rice-germ was done. One group was treated with AOM alone, four groups received the carcinogen and were fed the diets containing 2.5% rice-germ or 2.5% GABA-enriched defatted rice-germ for 5 (initiation phase) or 30 weeks (post-initiation phase), two groups were treated with rice-germ or GABA-enriched defatted rice-germ alone and one group was kept on the basal diet. At the termination of the study, dietary exposure to rice-germ during the initiation phase significantly reduced the incidence of colonic adenocarcinoma (71 versus 29%, P < 0.01). GABA-enriched defatted rice-germ or rice-germ during the post-initiation phase also decreased the frequency of colonic adenocarcinoma (71 versus 20%, GABA-enriched defatted rice-germ feeding, P < 0.01; 27%, rice-germ feeding, P < 0.01). These data suggest that constituents of rice-germ are possible dietary preventatives for human colon cancers.

Animals↗
PubMed1999

A regulatory domain (R1-R2) in the amino terminus of the N-methyl-D-aspartate receptor: effects of spermine, protons, and ifenprodil, and structural similarity to bacterial leucine/isoleucine/valine binding protein.

There are complex interactions between spermine, protons, and ifenprodil at N-methyl-D-aspartate receptors. Spermine stimulation may involve relief of proton inhibition, whereas ifenprodil inhibition may involve an increase in proton inhibition. We studied mutations at acidic residues in the NR1 subunit using voltage-clamp recording of NR1/NR2B receptors expressed in Xenopus oocytes. Mutations at residues near the site of the exon-5 insert, including E181 and E185, reduced spermine stimulation and proton inhibition. Mutation NR1(D130N) reduced sensitivity to ifenprodil by more than 500-fold, but had little effect on sensitivity to spermine and pH. Mutations at six other residues in this region of the NR1 subunit reduced the potency and, in some cases, the maximum effect of ifenprodil. These mutants did not affect sensitivity to pH, glutamate, glycine, or other hallmark properties of N-methyl-D-aspartate channels such as Mg2+ block and Ba2+ permeability. Residues in this region presumably form part of the ifenprodil-binding site. To model this region of NR1 we compared the predicted secondary structure of NR1 (residues 19-400) with the known structures of 1,400 proteins. This region of NR1 is most similar to bacterial leucine/isoleucine/valine binding protein, a globular amino acid binding protein containing two lobes, similar to the downstream S1-S2 region of glutamate receptors. We propose that the tertiary structure of NR1(22-375) is similar to leucine/isoleucine/valine binding protein, containing two "regulatory" domains, which we term R1 and R2. This region, which contains the binding sites for spermine and ifenprodil, may influence the downstream S1 and S2 domains that constitute the glycine binding pocket.

Amino Acid Sequence↗
PubMed1999

Stimulatory and inhibitory properties of aminoglycoside antibiotics at N-methyl-D-aspartate receptors.

The effects of aminoglycoside antibiotics on N-methyl-D-aspartate (NMDA) receptors were studied using voltage-clamp recording of recombinant NMDA receptors expressed in Xenopus oocytes. A number of aminoglycosides were found to potentiate macroscopic currents at heteromeric NR1A/NR2B receptors, but not at NR1A/NR2A, NR1A/NR2C, NR1A/NR2D, or NR1B/NR2B receptors. The degree of potentiation had a rank order neomycin B > paromomycin > gentamicin C > geneticin > kanamycin A > streptomycin. Potentiation was not seen with kasugamycin and spectinomycin. The degree of stimulation paralleled the number of the amino groups in the aminoglycosides. The stimulatory effects of aminoglycosides were more pronounced at subsaturating concentrations of glycine and at acidic pH, similar to the stimulatory effects of spermine. We measured the effects of aminoglycosides at mutant NMDA receptors to determine which amino acid residues in NMDA receptor subunits are involved in stimulation. Mutations that reduced or abolished spermine stimulation also reduced stimulation by aminoglycosides. Several aminoglycosides produced a weak voltage-dependent block of NMDA receptors, but the degree of inhibition did not appear to correlate with the number of amino groups in the molecule. The results suggest that aminoglycosides having more than three amino groups have stimulatory effects that are mediated through the spermine-binding site on NMDA receptors.

Aminoglycosides↗
PubMed1999

[A case of internal hernia through a defect in the falciform ligament treated with laparoscopic surgery].

A 22-year-old male was admitted to our hospital with abrupt onset of upper abdominal pain. Abdominal US and CT revealed dilatation of the small intestine between the abdominal wall and a lateral segment of the liver. After a diagnosis of an internal hernia through a defect in the falciform ligament, emergency surgery was performed. Laparoscopic investigation showed incarceration of the small intestine in a defect of the falciform ligament. After releasing an incarceration, the hernia orifice was opened to prevent relapse. He was discharged on the 4th postoperative day. Internal hernia through a defect in the falciform ligament is extremely rare, with six reported cases including our own in Japan. Characteristic images of abdominal US and CT enable preoperative diagnosis of this condition. Surgery should be performed at an early stage after onset. In patients with no prior history of surgery, laparoscopic techniques may be useful.

Adult↗
PubMed1998

pmp1+, a suppressor of calcineurin deficiency, encodes a novel MAP kinase phosphatase in fission yeast.

Calcineurin is a highly conserved and ubiquitously expressed Ca2+- and calmodulin-dependent protein phosphatase. The in vivo role of calcineurin, however, is not fully understood. Here, we show that disruption of the calcineurin gene (ppb1(+)) in fission yeast results in a drastic chloride ion (Cl-)-sensitive growth defect and that a high copy number of a novel gene pmp1(+) suppresses this defect. pmp1(+) encodes a phosphatase, most closely related to mitogen-activated protein (MAP) kinase phosphatases of the CL100/MKP-1 family. Pmp1 and calcineurin share an essential function in Cl- homeostasis, cytokinesis and cell viability. Pmp1 phosphatase dephosphorylates Pmk1, the third MAP kinase in fission yeast, in vitro and in vivo, and is bound to Pmk1 in vivo, strongly suggesting that Pmp1 negatively regulates Pmk1 MAP kinase by direct dephosphorylation. Consistently, the deletion of pmk1(+) suppresses the Cl--sensitive growth defect of ppb1 null. Thus, calcineurin and the Pmk1 MAP kinase pathway may play antagonistic functional roles in the Cl- homeostasis.

Amino Acid Sequence↗
PubMed1998

Aneurysmal rupture of the pancreaticoduodenal artery successfully treated by transcatheter arterial embolization.

We report a case of aneurysmal rupture of the pancreaticoduodenal artery successfully treated by transcatheter arterial embolization. A 61-year-old man with a history of hypertension underwent surgery at our hospital in November 1995 for local peritonitis caused by perforation of the sigmoid colon secondary to cancer. On the 9th postoperative day, he developed shock, with complaints of epigastric and back pain. Abdominal computed tomography showed an enhanced mass, thought to be a peripancreatic aneurysm. Emergency angiography demonstrated an aneurysm arising from the arcade of the anterior pancreaticoduodenal artery. After diagnostic angiography, transcatheter arterial embolization was performed. With steel coils, the anterior superior pancreaticoduodenal artery and anterior inferior pancreaticoduodenal artery were embolized near the origin of the aneurysm. Angiography 7 weeks later revealed no recanalization of the aneurysm and the absence of anomalous collateral vessels. The patient has been well for 19 months without re-bleeding or recurrence of sigmoid colon cancer. Transcatheter arterial embolization is an effective therapeutic approach for aneurysm of the pancreaticoduodenal artery and is the preferred initial treatment.

Aneurysm, Ruptured↗
PubMed1998

Exercise-induced acute renal failure in a girl with renal hypouricemia.

A 10-year-old Japanese girl developed acute renal failure following a 100-meter dash during physical training at school. After the run, she experienced intense pain in the loins with nausea and vomiting lasting more than 12 h. On the following morning, she was found to have mild proteinuria and acute renal failure (ARF). Serum creatinine and blood urea nitrogen were elevated, but the serum uric acid level was normal (3.1 mg/dL). With recovery of renal function over the ensuing days, hypouricemia (0.6 mg/dL) became evident in the patient. Although the pathophysiological association between renal hypouricemia and ARF is not known, oxygen free radicals have been implicated in the pathogenesis for ischemic-reperfusion ARF. Superoxide production by neutrophils stimulated by N-formyl methionine leucyl-phenylalanine was normal in the patient both before and following exercise. Pyrazinamide and probenecid tests were undertaken on both the patient and her parents, who had borderline hypouricemia, to determine their renal tubular handling of uric acid. Results showed that the patient and her mother had a subtotal reabsorption defect, while the father had defective postsecretory uric acid reabsorption.

Acute Kidney Injury↗
PubMed1998

G370C mutation in the FGFR3 gene in a Japanese patient with thanatophoric dysplasia.

Thanatophoric dysplasia (TD) is a sporadic lethal skeletal dysplasia with micromelic shortening of the limbs, relative macrocephaly, platyspondyly and reduced thoracic cavity. It has recently been reported that TD is caused by mutations in the FGFR3 gene. In the present study, we report a missense mutation in the FGFR3 gene in a Japanese patient with TD. The patient was noticed to have typical features of TD type 1 (TD1) at birth. The genomic DNAs of the patient and his parents were isolated from whole blood. DNA fragments of the FGFR3 gene were amplified by polymerase chain reaction, and directly sequenced. The patient was revealed to be heterozygous for a missense mutation G370C, changing codon 370 (GGC) encoding Gly to TGC encoding Cys, but his parents did not have the G370C mutation. The G370C mutation introduces an unpaired cysteine residue in the extracellular domain of FGFR3, which may result in formation of an intermolecular disulfide bond between two mutant FGFR3 monomers and their constitutive activation. In conclusion, we have identified the G370C mutation in the FGFR3 gene in a Japanese TD1 patient.

Alleles↗
PubMed1998

Antioxidant vitamin levels in plasma and low density lipoprotein of obese girls.

To investigate the antioxidant status of obese children, we analyzed beta-carotene and alpha-tocopherol levels in plasma and low density lipoprotein (LDL). We also analyzed the fatty acid composition of LDL as a substrate for oxidative stress. The plasma beta-carotene and alpha-tocopherol levels were relatively lower in obese girls than in normal controls. However, the plasma alpha-tocopherol/lipids ratio was significantly lower in obese girls than in normal controls. Both LDL beta-carotene and LDL alpha-tocopherol levels were significantly lower in obese girls than in normal controls, although no obvious differences were observed in plasma levels. In obese girls LDL contained more polyunsaturated fatty acid (PUFA) compared with normal controls. When the peroxidizability index (PI) was calculated to estimate the susceptibility of lipids to oxidative stress, obese girls had significantly higher PI values than normal controls. Both the LDL beta-carotene/PI ratio and the LDL alpha-tocopherol/PI ratio were significantly lower in obese girls than in normal controls. These results indicate the increased susceptibility of LDL to oxidative stress in obese girls which may promote atherosclerosis later in life.

Adolescent↗