Biomedical subjects

Akira Ohtsuru

Publications and source records attributed to Akira Ohtsuru.

41 records · Page 3Linked to original sources

PubMed2002

Expression of receptor-type tyrosine kinase, Axl, and its ligand, Gas6, in pediatric thyroid carcinomas around chernobyl.

Protein-tyrosine kinases (PTKs) play a crucial role in regulating thyroid cell growth and differentiation. It is known that PTKs are activated by ionizing radiation, but the critical pathways through ionizing radiation-induced malignant transformation are not well defined. The Axl protein is a member of a new family of receptor tyrosine kinases, which the ligand, Gas6, a protein S-related molecule, has recently been identified. We previously clarified the expression of Axl and mitogenic action of Gas6 in thyroid carcinoma cells. To investigate the involvement of Gas6-Axl signaling in pediatric thyroid carcinoma further, we examined tissues obtained from 17 patients with thyroid papillary carcinomas from Gomel, Belarus, by immunohistochemistry and in situ hybridization. Axl and Gas6 were overexpressed in 76.5% and 70.6 % of cases, respectively. Solid component and invasive front tended to overexppress Gas6 and Axl in papillary carcinomas. Eighty-five percent of Axl positive cases coexpressed Gas6. In situ hybridization also confirmed the presence of axl mRNA in thyroid carcinoma tissues. These findings suggest that Axl and Gas6 expression might be involved in childhood thyroid tumorigenesis around Chernobyl.

Child↗

PubMed2002

Norepinephrine enhances fibrosis mediated by TGF-beta in cardiac fibroblasts.

Cardiac fibrosis results from proliferation of interstitial fibroblasts and concomitant increased biosynthesis of extracellular matrix (ECM) components and is often complicated by cardiac hypertrophy. This study was conducted to investigate whether norepinephrine (NE) potentiates transforming growth factor-beta (TGF-beta)-induced cardiac fibrosis. The expression of the cardiac ECM proteins, plasminogen activator inhibitor-1 (PAI-1), fibronectin, and collagen type I, was examined by Western blotting using extracts from neonatal rat primary cardiac fibroblasts. In cardiac fibroblasts, treatment with a combination of NE and TGF-beta1 increased cell proliferation and ECM expression. Luciferase assays were conducted to clarify the effect of NE on TGF-beta signaling. TGF-beta1 (1 ng/mL) increased the specific signaling activity 2-fold, whereas the combination of NE (10 micro mol/L) and TGF-beta1 (1 ng/mL) resulted in an approximate 10-fold increase in specific signaling activity. We confirmed that treatment with NE markedly enhances TGF-beta-induced phosphorylation of activating transcription factor 2 (ATF-2). These results indicated that NE has a synergistic effect on TGF-beta signaling. To determine whether this activation by NE was mediated by the TGF-beta1 receptor, we used a dominant negative vector of the TGF-beta1 type II receptor, and the synergistic effects were inhibited. Furthermore, this synergistic effect was attenuated by a specific inhibitor of p38, SB203680. These data indicate that NE enhances cardiac fibrosis through TGF-beta1 post-receptor signaling, predominantly via the p38 MAP kinase pathway.

Activating Transcription Factor 2↗

PubMed2002

A histone deacetylase inhibitor enhances killing of undifferentiated thyroid carcinoma cells by p53 gene therapy.

Mutation of the p53 tumor suppressor gene is recognized to be a key event in the development of the highly aggressive behavior of undifferentiated or anaplastic thyroid carcinomas. Attempts to treat these carcinomas with p53 gene therapy have, however, been largely unsuccessful. Since epigenetic changes such as histone deacetylation are associated with loss of thyroid differentiation, we have evaluated the potential of combining p53 gene therapy with exposure to the histone deacetylase inhibitor (HDAC-1), depsipeptide. We used two carcinoma cell lines: FRO cells that express very low levels of p53 and WRO cells producing a dominant negative p53. A p53 response element luciferase assay showed that stimulation of p53 transcriptional activity by the combined treatment with the HDAC-1 and p53 was 10 to 100 times greater than with p53 alone. Western blot analysis demonstrated that the HDAC-1 increased the expression of acetylated histones, as well as of p21(cip1/waf1), but did not affect levels of total histone and endogenous p53. The combined treatment was much more effective than either treatment alone in inhibiting the growth of both cell lines, and flow cytometric analysis suggested that this was due to an increase in the sub-G1 apoptotic population. Our findings indicate that HDAC-1 enhances apoptotic killing by p53 transfer, and suggest that this combination strategy may be useful in treating undifferentiated thyroid carcinomas.

Acetylation↗

PubMed2002

Autocrine/paracrine involvement of parathyroid hormone-related peptide in vascular leiomyoma.

Vascular leiomyomas are believed to arise from the smooth muscle of blood vessels and are characterized by the proliferation of vascular smooth muscle cells (VSMC) and numerous slit-like vascular lumens. Parathyroid hormone (PTH)-related peptide (PTHrP) plays an important role in local autocrine and/or paracrine regulation of cellular growth and function in VSMC. To investigate the interaction between VSMC and endothelial cells, we evaluated the distribution of PTHrP and PTH/PTHrP-receptor in 10 vascular leiomyomas of the skin by immunohistochemistry and in situ hybridization (ISH) of paraffin-embedded specimens. Both immunohistochemistry and ISH revealed that PTH/PTHrP-receptors are expressed in endothelial cells lining areas with slit-like vascular lumens and very weakly expressed in proliferating VSMC in all vascular leiomyomas. On the other hand, PTHrP itself was localized mainly in proliferating VSMC. These results support the hypothesis that PTHrP acts through the PTH/PTHrP-receptor via an autocrine and/or paracrine mechanism from VSMC to endothelial cells in the formation of characteristic microenvironments of vascular leiomyoma cell composition.

Adult↗

PubMed2002

Distinctive gene expression of receptor-type tyrosine kinase families during rat hepatocarcinogenesis.

Growth factor receptor tyrosine kinase signaling plays key roles in regulating growth of normal hepatocytes, however, which receptor-type tyrosine kinase (RTK) is involved in hepatocarcinogenesis remains undetermined. The aim of this study was to characterize the expression of these receptors in different stages of rat liver carcinogenesis. We compared the expression profile of RTK genes in rat normal liver and diethylnitrosamine-induced hepatoma tissues using a homology cloning method with degenerated primers. In situ hybridization, immunohistochemical staining, and RT-PCR were performed to analyze the cell type-specific expression of target RTKs during the chemically-induced hepatocarcinogenesis. Sequence analysis of 459 clones identified 23 different RTK genes. The Tie-2, c-Met, and Flk-1 genes were the most abundant RTK genes cloned in rat hepatoma compared to normal liver. In situ hybridization and immunohistochemical studies showed overexpression of c-Met and Flk-1 in GST-P positive preneoplastic lesions as well as neoplastic lesions. Tie-2 was expressed not only in endothelial cells but also in so-called oval cells, which are thought to be liver stem cells. Tie-2 ligand, angiopointin-1, mRNA was detected in both normal livers and hepatoma cells/tissues. In contrast, angiopoietin-2 mRNA was detected only in hepatoma tissues. These results indicate that c-Met, Tie-2 and Flk-1 signals play important roles in different stages of chemically-induced hepatocarcinogenesis. Distinctive gene expression of RTK may contribute to epigenic implication of hepatoma formation.

Amino Acid Sequence↗