Gene expression network for tumor suppression

抑制肿瘤的基因表达网络

• 批准号: 12219204
• 负责人: TANIGUCHI Tadatsugu
• 金额: $ 261.06万
• 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 on Priority Areas
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12219204/
• 关键词: Interferon; IRF family; Noxa; p53; dendritic cells; apoptosis; osteoclast; RANKL; TLR3; 発がん抑制; Stat1; インターフェロン受容体; ウイルス感染; シグナルクロストーク; 破骨細胞分化; RANKL; IRFファミリー転写因子

In the current study, we have made multifaceted approach to elucidate molecular mechanisms for oncogenesis, by analyzing not only the interrelationships between molecules which are involved in tumor suppression but also the gene expression network from both genetic and epigenetic aspects. Specifically, we found several important roles of "weak signal" by constitutively produced IFN-α/β in IFN-γ or IL-6-mediated cellular response as well as regulatory systems for cancer prevention. We also found a novel cross-talk mechanism between RANKL and IFN-γ, and clarified the regulatory role of the IFN system in osteoclast differentiation, which provided its putative therapeutic application to bone destruction by metastatic tumors. Development of autoimmune-like disease was observed in mice lacking IRF-2, which is an attenuator of IFN-a/β signaling. Further analyses revealed the role of IFN-α/β signaling in the regulation of CD8^+ T cell response. In these IRF-2-deficient mice, such hyperactivati … More on of IFN-α/β signaling affects normal differentiation of dendritic cells. IFN-α/β signaling is also found to be indispensable during DC maturation. Furthermore, it was demonstrated that another IRF-family member, IRF-7, is an essential transcriptional factor for the IFN induction in plasmacytoid DCs in response to unmethylated DNA (CpG), which is known to be a potent adjuvant for anti-tumor immunity. And we found a spaciotemporal regulation, by which plasmacytoid DCs are capable to produce IFN-α/β at high levels. On the other hand, IRF-5 is also found to be essentially involved in the CpG-induced production of proinflammatory cytokines. In addition, we identified novel p53 target genes, Noxa and Reprimo, which are involved in p53-mediated apoptosis or cell cycle arrest, respectively. Further study by generating Noxa-deficient mice revealed that Noxa may be a beneficial therapeutic target since it undergoes selective apoptosis in oncogene-expressing cells. Finally, we found an interrelationship between IFN-α/β signaling and p53-mediated response, which provided a novel aspect in terms of a linkage between tumor suppression and immunity.Taken together, we believe that these research accomplishments contribute to some advance in understanding molecular mechanisms underlying tumor suppression, and provide a molecular basis for their clinical applications. Less

在目前的研究中，我们采取了多方面的方法来阐明肿瘤发生的分子机制，不仅分析了参与肿瘤抑制的分子之间的相互关系，而且从遗传和表观遗传方面分析了基因表达网络。具体来说，我们发现了组成型产生的IFN-α/β在IFN-γ或IL-6介导的细胞反应以及癌症预防的调节系统中的几个重要作用。我们还发现了RANKL和IFN-γ之间的一种新的串扰机制，并阐明了IFN系统在破骨细胞分化中的调节作用，这为其治疗转移性肿瘤引起的骨破坏提供了假定的治疗应用。在缺乏 IRF-2 的小鼠中观察到类似自身免疫性疾病的发展，IRF-2 是 IFN-a/β 信号传导的减弱剂。进一步的分析揭示了 IFN-α/β 信号传导在调节 CD8^+ T 细胞反应中的作用。在这些 IRF-2 缺陷小鼠中，IFN-α/β 信号传导的过度激活会影响树突状细胞的正常分化。还发现 IFN-α/β 信号传导在 DC 成熟过程中是不可或缺的。此外，研究还证明，IRF 家族的另一个成员 IRF-7 是浆细胞样 DC 响应未甲基化 DNA (CpG) 诱导 IFN 的重要转录因子，而 CpG 是抗肿瘤免疫的有效佐剂。我们发现了一种时空调节，通过这种调节，浆细胞样 DC 能够产生高水平的 IFN-α/β。另一方面，IRF-5 也被发现主要参与 CpG 诱导的促炎细胞因子的产生。此外，我们还鉴定了新的 p53 靶基因 Noxa 和 Reprimo，它们分别参与 p53 介导的细胞凋亡或细胞周期停滞。通过生成 Noxa 缺陷小鼠进行的进一步研究表明，Noxa 可能是一个有益的治疗靶点，因为它在癌基因表达细胞中经历选择性凋亡。最后，我们发现了IFN-α/β信号传导和p53介导的反应之间的相互关系，这为肿瘤抑制和免疫之间的联系提供了一个新的方面。总之，我们相信这些研究成果有助于理解肿瘤抑制的分子机制，并为其临床应用提供分子基础。较少的

项目成果

Sato,M.: "The IFN system and IRF transcription factors ; studies from gene knockout mice."Cytokine Growth Factor Rev.. (in press). (2001)

Sato,M.：“IFN 系统和 IRF 转录因子；基因敲除小鼠的研究。”《细胞因子生长因子 Rev.》（出版中）。

Noxa, a BH3-only member of the Bcl-2 family, and candidate mediator of p53-induced apoptosis.

Noxa 是 Bcl-2 家族中仅包含 BH3 的成员，也是 p53 诱导的细胞凋亡的候选介质。

• 发表时间: 2000
• 期刊: Science 288
• 作者: Oda;E.;Ohki;R.;Murasawa;H.;Nemoto;J.;Shibue;T.;Yamashita;T.;Tokino;T.;Taniguchi;T.;Tanaka;N.
• 通讯作者: N.

Honda, K., Sakaguchi, S., Nakajima, C., Watanaba, A., Yanai, H., Matsumoto, M., Ohteki, T., Kaisho, T., Takaoka, A., Akira, S., Seya, T., Taniguchi, T.: "Selective contribution of IFN-α/β signaling to the maturation of dendritic cells induced by double-st

Honda, K.、Sakaguchi, S.、Nakajima, C.、Watanaba, A.、Yanai, H.、Matsumoto, M.、Ohteki, T.、Kaisho, T.、Takaoka, A.、Akira, S.、 Seya, T., Taniguchi, T.：“IFN-α/β 信号传导对双链诱导的树突状细胞成熟的选择性贡献

Shibue, T., Takeda, K., Oda, E., Tanaka, H., Murasawa, H., Takaoka, A., Morishita, Y., Akira, S., Taniguchi, T., Tanaka, N.: "Integral role of Noxa in p53-mediated apoptotic response"Genes.Dev.. 17. 2233-2238 (2003)

Shibue, T.、Takeda, K.、Oda, E.、Tanaka, H.、Murasawa, H.、Takaoka, A.、Morishita, Y.、Akira, S.、Taniguchi, T.、Tanaka, N.：

Taniguchi T, Takaoka A.: "The interferon-alpha/beta system in antiviral responses : a multimodal machinery of gene regulation by the IRF family of transcription factors"Current Opinion in Immunology. 314巻・1号. 111-116 (2002)

Taniguchi T，Takaoka A.：“抗病毒反应中的干扰素-α/β 系统：转录因子 IRF 家族的基因调控多模式机制”，《免疫学最新观点》，第 314 卷，第 111-116 期。 2002）