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

不同的接收器组件之间的串扰通常对于另一个人放大，抑制或调节给定的受体信号通路很重要，这对于产生细胞反应的多样性至关重要。在这项研究中，我们感觉到探索细胞因子信号转导的新型调节机制，特别是在膜结构域可能参与信号效率，特异性和交叉谈话中的细胞因子信号中。 In this context, we previously reported on the critical role of the IFN-α/β signalling complex, generated by consistently 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信号传导。细胞因子。此外，这些结果表明，这些膜结构域在细胞因子信号期间起作用，是这些受体成分的信号脚手架。通过这些研究，我们证明了IFN-α/β弱信号传导的独特阶段，这是在较低水平的情况下始终产生的。实际上，我们还发现，这种弱信号还有助于响应病毒感染而扩增IFN-α/β的产生。因此，在我们提出的作为“改进系统”的背景下描述的这种弱信号传导为宿主防御中的更有效，更强大的信号传导提供了基础。我们还显示了构成型弱的IFN-α/β信号传导在抑制发电机中的可能作用，就独特的肿瘤系统而言。此外，我们在肿瘤抑制中发现了IFN-α/β信号传导与p53响应之间的一种新的相互关系，这可能为IFN在肿瘤抑制中的直接影响提供了一种可能的基本机制。引起癌症或自身免疫性疾病但治疗应用的潜在信号方面较少