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Biomedical subjects

I Gotoh

Publications and source records attributed to I Gotoh.

18 recordsLinked to original sources
PubMed2000

Identification and characterization of a novel MAP kinase kinase kinase, MLTK.

The MAPK cascades regulate a wide variety of cellular functions, including cell proliferation, differentiation, and stress responses. Here we have identified a novel MAP kinase kinase kinase (MAPKKK), termed MLTK (for MLK-like mitogen-activated protein triple kinase), whose expression is increased by activation of the ERK/MAPK pathway. There are two alternatively spliced forms of MLTK, MLTKalpha and MLTKbeta. When overexpressed in cells, both MLTKalpha and MLTKbeta are able to activate the ERK, JNK/SAPK, p38, and ERK5 pathways. Moreover, both MLTKalpha and MLTKbeta are activated in response to osmotic shock with hyperosmolar media through autophosphorylation. Remarkably, expression of MLTKalpha, but not MLTKbeta, in Swiss 3T3 cells results in the disruption of actin stress fibers and dramatic morphological changes. A kinase-dead form of MLTKalpha does not cause these phenomena. Inhibition of the p38 pathway significantly blocks MLTKalpha-induced stress fiber disruption and morphological changes. These results suggest that MLTK is a stress-activated MAPKKK that may be involved in the regulation of actin organization.

3T3 Cells↗
PubMed1999

Control of the cell morphology and the S phase entry by mitogen-activated protein kinase kinase. A regulatory role of its n-terminal region.

The mitogen-activated protein kinase kinase (MAPKK)/MAP kinase (MAPK) cascade plays an important role in the growth control of mammalian cells. We have found that expression of constitutively active MAPKK induces rapid morphological changes of fibroblastic cells, which are accompanied by disruption of stress fibers and disappearance of focal adhesions. These changes took place under the conditions that inhibited cellular Ras function, suggesting a linkage between the MAPK cascade and the control of cell morphology. We further show that constitutively active MAPKK can induce expression of endogenous Fos protein, an immediately early gene product, and cause the S phase entry of G0-arrested cells. Finally, expression of the N-terminal fragment of MAPKK which encompasses the nuclear export signal sequence and the MAPK-binding site blocked both the serum-induced S phase entry of quiescent cells and the oncogenic Ras-induced morphological changes. All these results demonstrate that MAPKK is one of key molecules involved in the control of both cell morphology and cell proliferation and suggest an important role for the N-terminal region of MAPKK in the regulation of the MAPK signaling.

3T3 Cells↗
PubMed1999

Prediction of the development of hepato-cellular-carcinoma in patients with liver cirrhosis by the serial determinations of serum alpha-L-fucosidase activity.

OBJECTIVE: Evaluation of the usefulness of the serial determinations of serum alpha-L-fucosidase (AFU) activity for prediction of the development of hepatocellular carcinoma (HCC) was performed. METHODS AND PATIENTS: Serum AFU activity was determined monthly for 42 months in 73 patients with liver cirrhosis (LC). RESULTS: HCC was diagnosed in 27 patients by means of ultrasonography during this observation period. In 23 (85%) of the 27 patients, serum AFU activity was found to exceed 700 nmole/ml/h during the LC stage. HCC developed within a few years in 23 (82%) of 28 LC patients with AFU activity exceeding 700 nmole/ml/h, in contrast, it developed in only 4 (9%) of 45 LC patients with AFU activity below 700 nmole/ml/h. AFU activity was already elevated in 23 (85%) of 27 patients at least 6 months before the detection of HCC by ultrasonography. CONCLUSION: It is conceivable that the development of HCC can be predicted by means of serial determinations of serum AFU activity in patients with LC.

Carcinoma, Hepatocellular↗
PubMed1998

Hepatocellular carcinomas infected with the novel TT DNA virus lack viral integration.

A novel DNA virus designated TT virus (TTV) was cloned from a patient with posttransfusion hepatitis and is thought to be a new hepatitis virus. At present, hepatitis B virus (HBV) and hepatitis C virus (HCV) are known to induce hepatocellular carcinoma (HCC). But, actually, in Japan approximately 5 to 10% of HCCs are in HBV-negative and HCV-negative (NBNC) patients. In order to study the possible role of TTV in hepatocarcinogenesis, we investigated the frequency of the TTV genome in liver tissue of 20 HCC patients. As a result, 3 of 8 NBNC HCC patients and 5 of 12 HBV- or HCV-associated HCC patients were TTV positive, and TTV was shown not to be specific for NBNC HCC. For all TTV-positive patients, we also confirmed that the TTV genome was not integrated into host hepatocyte DNA.

Aged↗
PubMed1998

A cross-validation of the European Organization for Research and Treatment of Cancer QLQ-C30 (EORTC QLQ-C30) for Japanese with lung cancer.

The EORTC QLQ-C30 was developed in English-speaking cultures. To determine if this instrument could cross a broad cultural divide and be used in Japan, the cross-cultural validity of its Japanese version was estimated. In evaluating psychometric testing, internal consistency by Cronbach's alpha, item-discrimination by multitrait scaling analysis, and validity analysis with ECOG performance score (PS) and Karnofsky Performance Status Scale (KPS) were performed. The QLQ-C30 (version 1.0) was given to 105 patients with lung cancer. Although the response rate was low in patients with PS 4, the questionnaire was well accepted by patients with PS 0-3. The Japanese QLQ-C30 has a weak scale of role functioning in terms of item discriminative validity. It also has a weak scale of cognitive functioning in items of discriminative validity and internal consistency. However, known-groups comparison showed the expected clinical validity with PS for all the scales except for financial impact, and longitudinally clinical validity with KPS was shown in scales of cognitive functioning, fatigue, and nausea and vomiting. Multitrait scaling analysis showed that the predicted scales constituting quality of life (QOL) in the English-speaking culture were extracted from the Japanese QLQ-C30, and found to be valid in Japan, indicating its possible usefulness as an instrument that is universally applicable across cultures.

Cross-Cultural Comparison↗
PubMed1998

[Signal transductions by the MAP kinase cascades].

The classical mitogen-activated protein(MAP) kinase cascade is one of the central intracellular signaling pathways that play a crucial role in cell proliferation, cell differentiation, cell transformation, and many other cellular responses. Two novel MAP kinase cascades, the SAPK/JNK cascade and the p38/MPK2 cascade, were identified, and were shown to function in various stress responses and apoptotic processes. Intracellular distribution of classical MAP kinase kinase (MAPKK/MEK) is regulated by its nuclear export signal (NES) which may function to suppress malignant cell transformation. CRM1 protein has been identified as a receptor for leucine-rich NES. CRM1 binds to CAN/NUP214, one of nucleopore proteins, which has been suggested to be involved in myeloid leukemia. Thus, the nuclear export system may be by somehow related to cancer development.

Animals↗
PubMed1997

A novel regulatory mechanism in the mitogen-activated protein (MAP) kinase cascade. Role of nuclear export signal of MAP kinase kinase.

Mitogen-activated protein kinase (MAPK) kinase (MAPKK, also known as MEK), a direct activator for MAPK/extracellular signal-regulated kinase, localizes to the cytoplasm excluded from the nucleus during signal transmission. This nuclear exclusion of MAPKK is directed by its nuclear export signal (NES), but its physiological significance has been unknown. We have found that disruption of the NES dramatically potentiates the ability of constitutively active MAPKK to induce morphological changes and malignant transformation of fibroblastic cells. Readdition of the NES sequence reversed the effects induced by the NES disruption. Moreover, we observed that a dramatic increase of activated MAPK in the nucleus was induced by the NES-disrupted MAPKK and that coexpression of MAPK phosphatase-1 (CL-100) or a kinase negative form of MAPK counteracted the phenotypes induced by the NES-disrupted MAPKK, indicating the crucial role of MAPK in the responses. These findings reveal a novel regulatory role of the NES of MAPKK that may be essential for proper signal transductions.

Animals↗
PubMed1996

Cytoplasmic localization of mitogen-activated protein kinase kinase directed by its NH2-terminal, leucine-rich short amino acid sequence, which acts as a nuclear export signal.

Mitogen-activated protein kinase (MAPK) is activated in cytoplasm in response to extracellular signals and then is translocated to nucleus. A directed activator for MAPK, MAPK kinase (MAPKK), stays in cytoplasm to transmit the signal from the plasma membrane to MAPK. Here we show that MAPKK contains a short amino acid sequence in the N-terminal region (residues 32-44), which acts as a nuclear export signal (NES) and thus is required for cytoplasmic localization of MAPKK. This NES sequence of MAPKK, like that of protein kinase inhibitor of cAMP-dependent protein kinase or Rev, is rich in leucine residues, which are crucial for the NES activity. Furthermore, the NES peptide of protein kinase inhibitor, as well as the NES peptide of MAPKK, inhibited the nuclear export of ovalbumin conjugated to the NES peptide of MAPKK. These results may suggest a common mechanism of nuclear export using a general leucine-rich NES.

Amino Acid Sequence↗
PubMed1993

Induction chemoradiotherapy followed by surgery for stage III non-small cell lung cancer.

Twenty-five patients with stage III, non-small cell lung cancer were treated with cisplatin-based chemotherapy and thoracic radiation therapy followed by surgery. Thirteen patients had stage IIIA disease and 12, stage IIIB disease. The chemotherapy and radiotherapy were intensively combined with only a few days' interval between them. Radiation therapy delivering a total dose of 50-70 Gy was started 10 days after the beginning of chemotherapy. A few additional courses of chemotherapy were repeated until a thoracotomy was performed. All but two surgically-treated patients underwent tumor resection, with 19 lobectomies and four pneumonectomies. Eighteen patients underwent curative and five, non-curative resections. Pathological examination of the resected specimen provided accurate intrathoracic information. Six patients (24%) showed a pathologically complete response, with no cancer cells detected in the resected specimens. Severe postoperative complications occurred in five patients (20%), with one death. The disease recurred in five of the 18 patients who underwent a curative resection. A second primary tumor developed in two other patients. Seventeen patients (68%) are alive, with a median follow-up of 37 months after thoracotomy. The estimated three-year survival was 67% for all patients.

Adult↗
PubMed1988

Carrier detection for adrenoleukodystrophy by high-performance liquid chromatography.

With a newly devised method of high-performance liquid chromatography (HPLC), we scrutinized lipid extraction of very-long-chain fatty acids of cultured skin fibroblasts from obligate (n = 4) and possible (n = 3) carriers for adrenoleukodystrophy (ALD) in order to establish the best method to detect a carrier for the ALD gene. All four methods (total esterified fatty acids, total fatty acids with acetonitrile-HCl, total fatty acids with methanolic-HCl, and triacylglycerol fraction) were applicable to carrier detection, but from the standpoint of simplicity and sensitivity, the method using total fatty acids with acetonitrile-HCl seemed to be the best. This is the first study of ALD carrier detection in which cultured skin fibroblasts are investigated using HPLC as an analytical method.

Adrenoleukodystrophy↗
PubMed1984

Replacement of the anterior cruciate ligament by an allogeneic tendon graft. An experimental study in the dog.

The revascularisation and remodelling of allografts used to replace the anterior cruciate ligament in the canine knee were studied by microangiographic, histological and biomechanical methods. The 26 allografts were obtained from the patellar tendons of other dogs and were stored by deep freezing. In a control study a strip of patellar tendon from the same leg was used as an autologous free graft. Microangiography showed that the allografts had been revascularised from the sixth postoperative week, and had later developed an intrinsic vascular pattern similar to that of a normal anterior cruciate ligament. Histologically, the allograft regained a fibrous framework similar to that of a normal ligament, and showed no evidence of immunological rejection. Biomechanical tests on the allograft replacements showed that their mean maximum tensile strength at 30 weeks was about 30% of that of the control ligaments. There were no significant differences between the mechanical properties of the allografts and the autografts.

Angiography↗