PubMed Health⌕ Search

Biomedical subjects

O Tetsu

Publications and source records attributed to O Tetsu.

10 recordsLinked to original sources
PubMed2005

Cancer targets in the Ras pathway.

Ras proteins play a direct causal role in human cancer and in other diseases. Mutant H-Ras, N-Ras, and K-Ras occur in varying frequencies in different tumor types, for reasons that are not known. Other members of the Ras superfamily may also contribute to cancer. Mutations also occur in downstream pathways, notably B-Raf, PTEN, and PI 3' kinase: These pathways interact at multiple points, including cyclin D1, and act synergistically. In some cases mutations in Ras and effectors are mutually exclusive; in other cases, they coexist. Drugs blocking elements of the pathway are in different stages of clinical development. One of these, the Raf kinase/VEGF-R2 inhibitor Sorafenib, has already been approved for treatment of renal cancer and is being tested in other indications. However, therapeutic targets in the Ras pathway have not yet been fully validated as bona fide targets.

Antineoplastic Agents↗
PubMed2001

A mammalian two-hybrid system for adenomatous polyposis coli-mutated colon cancer therapeutics.

Colon cancer cells frequently lose expression of the tumor suppressor adenomatous polyposis coli (APC). As result, beta-catenin accumulates and activates transcription of Tcf-responsive genes. Here we describe a novel mammalian two-hybrid system that selectively kills APC-mutated cells. This system consists of GAL4/beta-catenin, VP16/Tcf4, and a gene that is transcribed when GAL4 and VP16 associate. In APC-mutated human colon cancer cells, such as SW480, GAL4/beta-catenin accumulates, and in the presence of VP16/Tcf4, induces high levels of expression of the reporter gene. Expression of wild-type APC reduced GAL4/beta-catenin and intact beta-catenin levels and inhibited reporter gene expression. In colon cancer cells such as SW48 that have wild-type APC, GAL4/beta-catenin was degraded, and expression levels of the output gene were low. Replacement of the reporter gene with a suicide gene resulted in selective killing of SW480 cells. This system may be applicable for broader use of gene therapy by targeting diseases that involve protein degradation.

Adenomatous Polyposis Coli Protein↗
PubMed2001

Method for screening ecdysone-inducible stable cell lines.

Ecdysone-inducible systems are useful tools to study the function of various genes in different types of mammalian cells. However, it is technically difficult to establish stable cell lines. This is partly because the conditional expression system requires the expression of two or more components driven by different kinds of promoters. In this paper, we describe the use of a luciferase reporter gene system for rapid screening of cell lines that express the ecdysone and retinoid X receptors. Using this system, two human stable colon cancer cell lines, SW480/VgRXR and HCT116/VgRXR, were successfully generated. The expression of these receptors remained high after six months of continuous culturing. A tight regulation of gene induction in SW480/VgRXR was observed using 2 microM Ponasterone A. The gene induction was rapid and persistent. Our results demonstrated the advantage of establishing cell lines that continuously express high levels of ecdysone receptor proteins.

Animals↗
PubMed1999

Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells.

Mutations in the adenomatous polyposis coli (APC) tumour-suppressor gene occur in most human colon cancers. Loss of functional APC protein results in the accumulation of beta-catenin. Mutant forms of beta-catenin have been discovered in colon cancers that retain wild-type APC genes, and also in melanomas, medulloblastomas, prostate cancer and gastric and hepatocellular carcinomas. The accumulation of beta-catenin activates genes that are responsive to transcription factors of the TCF/LEF family, with which beta-catenin interacts. Here we show that beta-catenin activates transcription from the cyclin D1 promoter, and that sequences within the promoter that are related to consensus TCF/LEF-binding sites are necessary for activation. The oncoprotein p21ras further activates transcription of the cyclin D1 gene, through sites within the promoter that bind the transcriptional regulators Ets or CREB. Cells expressing mutant beta-catenin produce high levels of cyclin D1 messenger RNA and protein constitutively. Furthermore, expression of a dominant-negative form of TCF in colon-cancer cells strongly inhibits expression of cyclin D1 without affecting expression of cyclin D2, cyclin E, or cyclin-dependent kinases 2, 4 or 6. This dominant-negative TCF causes cells to arrest in the G1 phase of the cell cycle; this phenotype can be rescued by expression of cyclin D1 under the cytomegalovirus promoter. Abnormal levels of beta-catenin may therefore contribute to neoplastic transformation by causing accumulation of cyclin D1.

Binding Sites↗
PubMed1998

Mammalian Polycomb group genes are categorized as a new type of early response gene induced by B-cell receptor cross-linking.

Polycomb group (PcG) genes were initially described in Drosophila melanogaster as regulators of the homeobox gene. Four mammalian homologues, mel-18, bmi-1, M33 and rae-28, are analyzed in this study. They not only regulate mammalian homeotic genes by analogy with their Drosophila counterparts, but also have some influence on the growth and differentiation of B lymphocytes. Here we report that these four mammalian PcG genes are rapidly induced after antigen-receptor cross-linking in B cells. Thus we would like to propose that mammalian PcG genes can be categorized as a new type of immediate early gene.

Animals↗
PubMed1998

mel-18 negatively regulates cell cycle progression upon B cell antigen receptor stimulation through a cascade leading to c-myc/cdc25.

mel-18 is a mammalian Polycomb group gene encoding a transcriptional repressor with tumor suppressive activity. Overexpression of mel-18 in mice results in cell cycle arrest of B cells upon B cell receptor stimulation with downregulation of c-myc. This phenotype is rescued in mel-18/c-myc double-transgenic mice, suggesting that c-myc locates downstream of mel-18. In mel-18 transgenic mice, the downregulation of cyclins D2 and E; CDK4, -6, and -7; and CDC25A causes the impairment in the activities of cyclin-dependent kinases, resulting in hypophosphorylation of the retinoblastoma protein. In contrast, the upregulation of c-Myc, CDC25, and CDC2/CDK2 kinase activities results in the augmentation of B cell proliferation in mel-18-deficient mice. We therefore propose that mel-18 negatively regulates the cell cycle through a c-myc/cdc25 cascade.

Animals↗
PubMed1997

The role of mel-18, a mammalian Polycomb group gene, during IL-7-dependent proliferation of lymphocyte precursors.

mel-18 is a mammalian homolog of Drosophila melanogaster Polycomb group genes. Mice lacking the mel-18 gene show a posterior transformation of the axial skeleton, severe combined immunodeficiency, and a food-passing disturbance in the lower intestine due to hypertrophy of the smooth muscle layer. In this study, the severe combined immunodeficiency observed in mel-18 mutant mice is correlated with the impaired mitotic response of lymphocyte precursors upon interleukin-7 stimulation. Strikingly, the axial skeleton and lymphoid phenotypes are identical in both mel-18 and bmi-1 mutants, indicating that the Mel-18 and Bmi-1 gene products might act in the same genetic cascade. These results suggest that mammalian Polycomb group gene products are involved in cell cycle progression in the immune system.

Animals↗
PubMed1993

A case of spontaneous intramural hematoma of the esophagus.

The authors experienced a case of spontaneous intramural hematoma of the esophagus (SIHE). This 44-year-old Japanese woman was admitted to our hospital because of chest pain accompanied by minimal hematemesis. Endoscopy revealed an elevated intraluminal bleeding bulge. Barium esophagograms showed a smooth and giant elevated intraluminal lesion. CT and MRI also revealed thickening of the esophageal wall. Fasting and intravenous hyperalimentation were prescribed on admission. The conditions improved and she became asymptomatic on the fifth day of hospitalization. Subsequent examinations by esophagography and endoscopy showed that the elevated lesion had disappeared and that the inflamed mucosal lesion had improved. The prognosis of cases of SIHE is excellent under conservative therapy, but close follow-up care is necessary.

Adult↗