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Studies about novel roles of the membrane domain in signal transduction systems

膜结构域在信号转导系统中新作用的研究

基本信息

批准号：
13680772
负责人：
TAKAOKA Akinori
金额：
$ 2.75万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

项目摘要

Cross talk between distinct receptor components is often important to amplify, suppress or modulate a given receptor signalling pathway by the other, and this is an aspect critical to generate diversity of cellular responses. In this study, we sought to explore a novel regulatory mechanism(s) in cytokine signal transduction, particularly in terms of the possible involvement of membrane domains in signalling efficiency, specificity and cross talk among cytokine signallings. In this context, we previously reported on the critical role of the IFN-α/β signalling complex, generated by constitutively produced IFN-α/(3, in IFN-γ signalling. As a result of the extended study, here, we found a novel cross talk between interferon (IFN)-α/β and interleukin (IL)-6 signallings, wherein the constitutive, weak IFN-α/β signalling also contributes to enhance the IL-6 signalling. The previous and present studies showed that the receptor components for IFN-α/β, IFN-γ, and IL-6 were concentrated in caveol … More ar membrane fractions, i.e., membrane domains. This suggests that these receptor components seem to be in close proximity to forma mulli-subunit complex, which may be termed "receptosome", so as to make efficient signalling for these cytokines. In addition, these results show a possibility that these membrane domains play a role as a signalling scaffold for these receptor components during the cytokine signalling.Through these series of studies, we demonstrated a unique facet of a weak signalling by IFN-α/β, which is constitutively produced at a low level in the absence of viral infection. In fact, we additionally found that this weak signal also contributes to amplification of IFN-α/β production in response to viral infection. Therefore, this weak signalling, described in the context of what we propose as a "revving-up system", was found to provide a foundation for a more efficient and robust signalling in host defense.We also showed the possible role of the constitutive, weak IFN-α/β signalling in suppression of oncogenesis, in terms of a unique tumor urveillance system. Furthermore, we found a novel inter-relationship between IFN-α/β signalling and p53 response in tumor suppression, which may provide a possible underlying mechanism to the direct effect of IFN in tumor suppression.Taken together, we believe that these research accomplishments made progress in the study on the elucidation of advanced complex mechanisms for the regulation of cellular signalling events, and that further extended studies will provide any contributions not only to the elucidation of underlying signalling aspects which cause cancer or autoimmune diseases, but to their therapeutic applications Less

不同受体组分之间的串扰通常对于放大、抑制或调节另一种给定受体信号传导途径是重要的，并且这是产生细胞应答多样性的关键方面。在这项研究中，我们试图探索一种新的调节机制（S）在细胞因子信号转导，特别是在膜结构域的信号转导效率，特异性和细胞因子信号之间的串扰可能参与。在这种情况下，我们先前报道了IFN-α/β信号复合物的关键作用，该复合物由组成型产生的IFN-α/β在IFN-γ信号中产生。作为扩展研究的结果，在这里，我们发现了干扰素（IFN）-α/β和白细胞介素（IL）-6信号传导之间的新串扰，其中组成性弱IFN-α/β信号传导也有助于增强IL-6信号传导。以往和目前的研究表明，IFN-α/β、IFN-γ和IL-6的受体成分集中在Caveol中 ...更多信息 AR膜部分，即，膜结构域这表明这些受体组分似乎非常接近于形成多亚基复合物，其可以被称为“受体体”，从而为这些细胞因子提供有效的信号传导。此外，这些结果表明，这些膜结构域在细胞因子信号传导过程中作为这些受体组分的信号传导支架发挥作用的可能性。通过这些系列研究，我们证明了IFN-α/β的弱信号传导的独特方面，在没有病毒感染的情况下，IFN-α/β以低水平组成性产生。事实上，我们还发现这种弱信号也有助于响应病毒感染的IFN-α/β产生的放大。因此，这种弱信号，在我们提出的“加速系统”的上下文中被描述，被发现为宿主防御中更有效和更强大的信号提供了基础。我们还显示了组成性弱IFN-α/β信号在抑制肿瘤发生中的可能作用，就独特的肿瘤监测系统而言。此外，我们发现IFN-α/β信号通路与p53反应在肿瘤抑制中的新的相互关系，这可能为IFN直接抑制肿瘤提供了一个可能的潜在机制。综上所述，我们认为这些研究成果在阐明细胞信号事件调控的高级复杂机制方面取得了进展，进一步的扩展研究将不仅对阐明导致癌症或自身免疫性疾病的潜在信号传导方面，而且对它们的治疗应用做出贡献。