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Biomedical subjects

A Yoshimura

Publications and source records attributed to A Yoshimura.

At least 181 records · Page 10Linked to original sources
PubMed1994

Adenosine triphosphate-dependent transport of leukotriene C4 by membrane vesicles prepared from cisplatin-resistant human epidermoid carcinoma tumor cells.

BACKGROUND: Cisplatin accumulation is decreased in many cisplatin-resistant cells. An active efflux pump for cisplatin exists in cisplatin-resistant human epidermoid carcinoma cells (called KB cells). A previous study has suggested that the adenosine triphosphate (ATP)-dependent glutathione S-conjugate export pump (GS-X pump), which exports the bis-(glutathionato)-platinum (II) (GS-platinum) complex, could contribute to cellular resistance to cisplatin. PURPOSE: In this study, we examined whether the active efflux pump for cisplatin in the cisplatin-resistant KB cells is the GS-X pump and tested its activity by using an endogenous substrate, [3H]leukotriene C4 ([3H]LTC4). METHODS: Membrane vesicles were prepared from KB-3-1 (clone from parental KB cells) cells and from cisplatin-resistant KCP-4 (a mutant clone derived from KB-3-1 cells) cells. Using a filtration technique, we measured the uptake and transport of [3H]LTC4, a substrate for the GS-X pump, into membrane vesicles at 37 degrees C. RESULTS: The uptake of [3H]LTC4 in the membrane vesicles from both the KB-3-1 and KCP-4 cells was ATP-dependent. In contrast, the ATP-dependent transport of [3H]LTC4 was observed only in KCP-4 membrane vesicles but not in KB-3-1 membrane vesicles. The ATP-dependent transport was vanadate sensitive and was inhibited by GS-platinum complex but only marginally by cisplatin and glutathione and not by vincristine or verapamil. The nucleotide triphosphates, guanosine triphosphate, cytidine triphosphate, uridine triphosphate, and deoxythymidine triphosphate could be substituted for ATP but were less efficient. A nonhydrolyzable ATP analogue, adenosine 5'-(beta,gamma-methylene) triphosphate, was not effective. CONCLUSIONS: The transport of LTC4 in membrane vesicles prepared from KCP-4 cells was facilitated by an ATP-dependent pump that appeared very similar to the GS-X pump. IMPLICATIONS: Our study suggests that the GS-X pump is involved in the decreased accumulation of cisplatin in KCP-4 cells.

Adenosine Triphosphate↗
PubMed1994

Proliferation and erythroid differentiation through the cytoplasmic domain of the erythropoietin receptor.

Interaction of erythropoietin (EPO) and its membrane receptor induces the proliferation and differentiation of erythroid progenitors. The molecular mechanism of the EPO receptor-mediated signal transduction remains unclear because the cloned EPO receptor does not contain any enzyme-related or nucleotide-binding consensus sequences in its cytoplasmic domain. We have previously shown that epidermal growth factor (EGF) induces dimerization of a chimeric receptor carrying the extracellular domain of the EGF receptor linked to the cytoplasmic domain of the EPO receptor, resulting in producing proliferation signals in interleukin-3-dependent cells. Here we show that this chimeric receptor transmits an EGF-dependent erythroid differentiation signal in the EPO-responsive erythroleukemia cell line, TSA8. EGF as well as EPO had little effect on the proliferation of TSA8 cells expressing the chimeric receptor, but both of them induced globin synthesis in these cells. Moreover, a truncated chimeric receptor carrying the membrane proximal 127 amino acids of the cytoplasmic domain of the EPO receptor linked to the extracellular domain of the EGF receptor conferred EGF-dependent proliferation on Ba/F3 cells and globin induction on TSA8 cells. These findings indicate that the membrane proximal region of the cytoplasmic domain of the EPO receptor is sufficient to produce both proliferation and differentiation signals if it is properly activated by receptor dimerization.

Amino Acid Sequence↗
PubMed1994

Ligand-induced activation of chimeric receptors between the erythropoietin receptor and receptor tyrosine kinases.

Ligand-induced dimerization is a key step in the activation of receptor tyrosine kinases, including the epidermal growth factor receptor, stem cell factor receptor (c-kit), and colony-stimulating factor 1 receptor (c-fms). The erythropoietin receptor (EPOR), a member of the cytokine receptor family, contains no kinase motif and its activation mechanism remains unclear. Here we show that chimeric receptors carrying the extracellular domain of the epidermal growth factor receptor or c-kit linked to the cytoplasmic domain of the EPOR, transmitted epidermal growth factor or stem cell factor-dependent proliferation signals in an interleukin 3-dependent cell line. The chimeric receptors as well as the wild-type EPOR also mediated the ligand-induced tyrosine phosphorylation of a set of similar proteins. Moreover, erythropoietin triggered mitogenic signals of chimeric receptors carrying the extracellular domain of the EPOR linked to the tyrosine kinase of c-fms. These data demonstrate the interchangeability of domains between two distinct receptor families and suggest that ligand-induced dimerization is a key step in activating the EPOR.

Amino Acid Sequence↗
PubMed1994

GD2 ganglioside-specific monoclonal antibody reacts with murine cytotoxic T lymphocytes reactive with FBL-3N erythroleukaemia.

Ganglioside expression on cytotoxic T lymphocytes induced against the mouse erythroleukaemia line FBL-3N, was analysed, compared with that of naive T lymphocytes in the thymus, lymph nodes and spleen. Although normal uncultured and cultured T lymphocytes expressed no GD2, GD3 or GM2 gangliosides, cytotoxic T cells with CD4+CD8-, CD4-CD8+, and CD4-CD8- phenotypes reacted with anti-GD2 monoclonal antibody with various intensities. The reactivity with anti-GD2 was associated with the intensity of cytotoxic activity as analysed using cytotoxic T lymphocyte (CTL) clones established from the bulk CTLs of each phenotype. An increase of the mRNA expression of GM2/GD2 synthase gene was demonstrated by Northern blot hybridization using RNA extracted from thymocytes, spleen cells, Con A-treated spleen cells and various types of CTL cells. These results indicated that GD2 ganglioside expression might be associated with the functional differentiation of murine T lymphocytes.

Animals↗
PubMed1994

Immunochemical study of epidermal growth factor in rats with mercuric chloride-induced acute renal failure.

Urine contains high concentrations of epidermal growth factor (EGF), and EGF is a potent growth promoter for proximal tubular cells. In the present study, urinary and whole-kidney EGF levels were investigated in rats with mercuric chloride (HgCl2)-induced acute renal failure (ARF) using a specific radioimmunoassay for rat EGF to clarify changes in EGF after toxic injury. Male Wistar rats were given HgCl2 (2 mg/kg, subcutaneously) or saline. Serum urea nitrogen and creatinine levels were measured for 4 days after toxin administration. Forty-eight hours after toxic injury, urinary immunoreactive EGF levels in HgCl2-treated rats decreased significantly compared with control rats (1.62 +/- 0.15 versus 3.78 +/- 0.21 ng/mg creatinine; p < 0.01). Urinary immunoreactive EGF was at its lowest level 96 h after toxic injury (0.64 +/- 0.06 ng/mg creatinine; p < 0.001). Twenty-four hours after toxic injury, renal immunoreactive EGF levels increased significantly compared with control rats (22.04 +/- 2.12 versus 4.84 +/- 0.70 ng/g wet weight tissue; p < 0.001), and the increase persisted for as long as 48 h (13.36 +/- 1.61 ng/g wet weight tissue; p < 0.05). In summary, urinary immunoreactive EGF levels decreased and renal EGF levels increased in rats with HgCl2-induced ARF. These findings suggest that there is an impairment in the excretion of EGF in rats with HgCl2-induced ARF and that local paracrine production of EGF continues in ARF.

Acute Kidney Injury↗
PubMed1993

Progesterone and its metabolites: the potent inhibitors of the transporting activity of P-glycoprotein in the adrenal gland.

P-glycoprotein (P-gp) is a transmembrane glycoprotein responsible for the multidrug resistant (MDR) phenotype in various cancer cells. It has been shown that P-gp transports various kinds of anti-cancer agents as well as hydrophobic chemicals. Although P-gp is also expressed in normal human tissues, such as liver, kidney, and adrenal gland, its function and transporting substrates in these tissues are still unknown. In previous work, we demonstrated that some compounds in human plasma modulate the transporting activity of P-gp. We also found that P-gp is expressed at a high level in the bovine adrenal gland and that this tissue contains large amount of compounds which inhibit the transporting activity of P-gp. We purified such compounds from the adrenal gland by monitoring the ability to enhance the accumulation of [3H]vincristine in MDR cells. Two major compounds were purified and identified as progesterone and pregnenolone by nuclear magnetic resonance (NMR) analysis. Progesterone was the most potent and abundant compound that inhibited the transporting activity of P-gp among the compounds extracted from bovine adrenal gland with methanol. We also found that six authentic progesterone metabolites in the 5 beta-metabolic pathway but none in the 5 alpha-metabolic pathway were able to enhance the accumulation of [3H]vincristine in MDR cells and to inhibit [3H]azidopine photolabeling of P-gp in the adrenal gland. These results indicate that some progesterone metabolites can interact with P-gp and that stereoisomerism around carbon 5 of the progesterone metabolites is important for them to be recognized by P-gp.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1993

Expression of the multidrug transporter, P-glycoprotein, in renal and transitional cell carcinomas.

BACKGROUND: Renal cell carcinomas (RCC) respond poorly to anthracyclines, Vinca alkaloids, and other agents. P-glycoprotein is overproduced in multidrug-resistant cells and thought to function as an energy-dependent drug efflux pump. The authors thus examined the expression level of P-glycoprotein in RCC and transitional cell carcinomas (TCC). METHODS: P-glycoprotein was detected using immunoblotting with a monoclonal antibody against it, C219. RESULTS: Thirty-three of 38 patients with RCC and 3 of 17 patients with TCC had P-glycoprotein positive tumors. The expression level of P-glycoprotein in most of RCC was lower than that in the normal kidney tissues and that of P-glycoprotein in the TCC was very low. The size of P-glycoprotein in 14 RCC and 3 TCC was 5-10 kilodaltons smaller than in the normal renal tissues. The variation of P-glycoprotein size in the RCC was attributed to differential N-linked glycosylation. P-glycoprotein in a RCC was photolabeled by tritiated azidopine, and the labeling was inhibited by some organic agents. P-glycoprotein distributed on the apical or marginal cell surface of the RCC. CONCLUSIONS: These data show that P-glycoprotein was expressed in many RCC, and its expression level, glycosylation, and distribution were altered. These data also suggest that the P-glycoprotein in RCC had similar drug binding site(s) to that in multidrug-resistant cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1993

Rejection of an IA+ variant line of FBL-3 leukemia by cytotoxic T lymphocytes with CD4+ and CD4-CD8- T cell receptor-alpha beta phenotypes generated in CD8-depleted C57BL/6 mice.

FBL-3N is an MHC class II Ag+ variant line that was obtained spontaneously during maintenance of Friend virus-induced leukemia FBL-3 in an athymic C57BL/6 (B6) mouse. Inocula of FBL-3N, but not the parental FBL-3 tumor, regressed after initial growth in CD8-depleted, syngeneic B6 mice. The cellular mechanisms by which FBL-3N was rejected in these mice were investigated in this study. We demonstrated that CTL with both CD4+ and CD4-CD8-TCR-alpha beta phenotypes were generated in mixed lymphocyte tumor cell culture spleen cells obtained from CD8-depleted B6 mice that had rejected FBL-3N by in vitro stimulation with mitomycin C-treated FBL-3N. After adoptive transfer of these CTL that were generated in vitro into athymic B6 mice, challenge with the FBL-3N tumor resulted in tumor regression after its initial growth. Thus, CD4+ and CD4-CD8-TCR-alpha beta CTL mediated rejection of the FBL-3N tumor in CD8-depleted B6 mice. Furthermore, the findings that depletion of B6 mice of CD4+ cells in addition to CD8+ cells abrogated the rejection of FBL-3N and generation of CTL in mixed lymphocyte tumor cell culture spleen cells suggest that CD4+ cells were required not only as a source of CD4+ CTL, but also as helper cells for generation of CD4-CD8-TCR-alpha beta CTL. Tumor Ag recognition of CD4-CD8-TCR-alpha beta CTL was restricted to Db, like that of classical CD8+ CTL, but the restriction appeared to be less obligatory than that of CD8+ CTL.

Animals↗