Molecular mechanisms of abnormal differentiation and transcriptional regulation in cancer cel

本研究旨在阐明TRAF 6介导的NF-κB活化的分子机制以及NF-κB在肿瘤发生和恶性肿瘤中的作用。获得了以下结果。（1）HTLV-1的致癌Tax蛋白激活NF-κB，诱导细胞生长失调。我们的研究结果强烈提示Tax介导的NF-κ B活化不需要TAK 1和K63连接的NEMO的多聚泛素化。基于这些结果，我们提出了Tax激活NF-κB的新模型。（2）IL-1的高表达与肿瘤的恶性程度有关。我们发现，IL-1刺激导致TRAF 6催化的K63连接的TAK 1的多聚泛素化，这是TAK 1活化所必需的。我们进一步发现MEKK 3是TAK 1的重要上游激活因子，TRAF 6、MEKK 3和TAK 1以IL-1刺激依赖的方式形成信号复合物。我们提出了双相NF-κB激活模型，其中TAK 1依赖的RING通路先于TAK 1非依赖的锌通路。(3)We筛选出25个NF-κB靶基因，这些基因可能与肿瘤的恶性程度有关。（4）来源于乳腺癌、肺癌和胃癌的6个细胞系的生长依赖于NF-κ B活化，它们以IKKα依赖的方式生长。结果表明，参与非经典途径在其增殖。

We aimed to clarify molecular mechanisms of the TRAF6-mediated NF-κB activation and roles of NF-κB in oncogenesis and malignancy. The following results were obtained. (1)Oncogenic Tax protein of HTLV-1 activates NF-κB to induce dysregulated cell growth. In contrast to the cytokine-induced NF-κB activation, our results strongly suggest that Tax-mediated NF-κB activation does not require TAK1 and K63-linked polyubiquitination of NEMO. Based on these results we propose a novel model of NF-κB activation by Tax. (2)Enhanced expression of IL-1 is involved in malignancy of cancer. We found that IL-1 stimulation results in TRAF6-catalyzed K63-linked polyubiquitination of TAK1, which is essential for TAK1 activation. We further found that MEKK3 is an essential upstream activator of TAK1, and TRAF6, MEKK3 and TAK1 form signal complexes in an IL-1 stimulation-dependent manner. We propose the biphasic NF-κB activation model, in which the TAK1-dependent RING pathway precedes the TAK1-independent Zinc pathway. (3)We identified 25 NF-κB target genes that probably involved in cancer malignancy. (4)Six cell lines derived from breast, lung and gastric cancers, whose growth depends on NF-kB activation, grow in an IKKα-dependent manner. The result suggests involvement of the non-classical pathway in their proliferation.