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Ganglioside dependent return of TSH receptor function in a rat thyroid tumor with a TSH receptor defect.
No full textThe 1-8 rat thyroid tumor line with a thyrotropin and cholera toxin receptor defect and a deficiency in higher order membrane gangliosides is shown to regain both receptor functions with the in vivo resynthesis or the in vitro reconstitution of higher order gangliosides. Reconstitution was achieved by exposing primary cell cultures of the tumor to preparations of gangliosides from thyroid cells with functional thyrotropin receptor activity
5-aminolaevulinic acid/Photo-Dynamic Therapy and Gefitinib in Non Small Cell Lung Cancer cell lines: a potential strategy to improve Gefitinib therapeutic efficacy
No full textAbstract
OBJECTIVES:
Often, non-small cell lung cancers (NSCLC) respond only poorly to the tyrosine kinase inhibitor (TKI) gefitinib, which targets the epidermal growth factor receptor (EGFR), these poor responders EGFRs lacking activating mutations. In this study, we have attempted to improve TKI response of NSCLC cell lines (A549 and H1299) devoid of EGFR mutations, by combination of gefitinib and 5-ALA/photodynamic therapy (PDT).
MATERIALS AND METHODS:
Cells of the two lines were incubated with gefitinib (from 0.5 to 50 mm, for 48 h) then irradiated at doses ranging from 4 to 20 J/cm(2) ; 5-ALA concentration and incubation time were kept constant (1 mm for 3 h). We analysed cell viability, colony-forming efficiency, cell cycle parameters, proteasome and NF-??B activity and expression patterns of specific proteins, after individual or combined treatments.
RESULTS:
Effects (antagonistic, additive or synergistic) of combination treatment were evaluated using a predictive model (combination index) for expected interactive effects and results are consistent with mutual potentiation exceeding simple additivity. Investigation of molecular mechanisms underlying cytotoxic effects indicated that combination treatment impaired proteasome function, inhibited NF-??B transcriptional activity and hampered AKT pro-survival signalling.
CONCLUSIONS:
The results of this study show that poor response of cells devoid of EGFR activating mutations to TKIs, can be overcome by combining gefitinib with 5-ALA/photodynamic therapy (PDT)
Mevalonate controls cytoskeleton organization and cell morphology in thyroid epithelial cells.
No full textMevalonate controls cytoskeleton organization and cell morphology in thyroid epithelial cells.
No full textThe effect of evolution on homologous proteins: a comparison between the chromophore microenvironments of Italian water buffalo (Bos bubalus, L.) and sperm whale apomyoglobin
No full text[Conformational properties of buffalo apomyoglobin. IV. Dichroic activity in the short and long wave ultraviolet]
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Multicomponent structure of the thyrotropin receptor: relationship to Graves' disease.
No full textThe thyrotropin receptor is proposed to contain both a glycoprotein and a ganglioside component. Monoclonal antibodies have been developed against soluble thyroid TSH receptor preparations and using Graves' lymphocytes. These show that initial recognition of thyrotropin requires the glycoprotein component, but that monoclonal antibodies to this component block thyrotropin function (blocking antibodies) rather than mimic thyrotropin. Monoclonal antibodies which stimulate thyroid activity in cultured cell systems (cAMP increase) or mouse bioassays, all interact with gangliosides. Using monoclonal antibodies to the glycoprotein component of the thyrotropin receptor, we show that two protein bands, molecular weights 18,000-23,000 and 50,000-55,000, are precipitated from detergent-solubilized preparations. Using a crosslinking procedure with 125I-labeled thyrotropin, we show that thyrotropin binding is related to the disappearance of the 18,000-23,000 molecular weight band on sodium dodecylsulfate gels and the appearance of a 30,000-33,000 molecular weight thyrotropin-membrane component complex. Higher molecular weight thyrotropin-membrane complexes of 75,000-80,000 and 250,000 are visualized when binding studies are performed at pH 7.4 in physiologic medium; larger amounts of the 30,000-33,000 complex are evident at pH 6.0 in a low salt medium. It is thus proposed that the glycoprotein component of the thyrotropin receptor is composed of two subunits with apparent molecular weights of 18,000-23,000 and 50,000-55,000; that the 18,000-23,000 subunit interacts with thyrotropin; and that different receptor subunits can exist depending on in vitro binding conditions. Using monoclonal-stimulating antibodies or natural autoimmune IgG preparations from patients' sera, we show that stimulating antibodies exhibit species-specific binding to human thyroid ganglioside preparations. Individual components or determinants of the thyrotropin receptor structure with specific autoimmune immunoglobulins
The relationship of growth and adenylate cyclase activity in cultured thyroid cells: separate bioeffects of thyrotropin.
No full textUsing a clonal line of TSH-dependent functional rat thyroid cells, the effects of TSH on cAMP production and cell growth, as measured by cell number and [14C]thymidine incorporation, were compared. The withdrawal of TSH from the medium stopped the growth of cells, as measured by cell number. After 24 h in TSH-free medium, an acute challenge with 1 × 10-11 M pure TSH caused a 40-fold increase in the cAMP level; this response increased to greater than 80-fold as TSH withdrawal from the culture system was prolonged over 10 days. In contrast to these acute effects on cAMP levels, an increase in [14C]thymidine incorporation required 20-fold higher TSH concentrations and waned to an unresponsive level after 10 days of TSH withdrawal. After withdrawal of TSH from the medium for 10 days, readdition of TSH could return cell growth to normal rates only after a 2-day lag period. In terms of the lag, the TSH effect on cell number was paralleled by its effect on thymidine incorporation, not cAMP levels; (Bu)2-cAMP at concentrations as high as 1 × 10-3 M could not duplicate the effect of TSH on either cell number or thymidine incorporation. The effect of TSH on thymidine incorporation was blocked by anti-TSH, but not by an antibody to contaminant proteins in crude TSH preparations. Crude TSH could increase thymidine incorporation, but was nearly 1/100th less effective based on its bioactivity measurements, i.e. contained an inhibitor in addition to an activator of thymidine incorporation. The inhibitor activity affected the cAMP response in a parallel manner. These observations are consistent with separate bioeffects of TSH mediated through different domains of the TSH receptor or different transmission pathways. The data suggest that discriminant separation of these bioeffects in primary cultures of human thyroid cells, wherein TSH challenge augments cAMP production but fails to elevate [14C]thymidine incorporation, does not reflect the absence of a TSH mitogenic activity but, rather, demonstrates a condition wherein the TSH receptor is uncoupled from the message transmission pathway important for cell growth. The data also suggest that the TSH effect on cell growth requires an action beyond that of activating the adenylate cyclase syste
Effects of thyrotropin on the thyroid cell membrane: hyperpolarization induced by hormone-receptor interaction
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