Molecular mechanisms of abnormal differentiation and transcriptional regulation in cancer cel

本研究旨在阐明TRAF6介导的NF-κB活化的分子机制及其在肿瘤发生和恶性发展中的作用。得到了以下结果。(1)HTLV-1致癌Tax蛋白激活NF-κB，诱导细胞生长失调。与细胞因子诱导的NF-κB激活相反，我们的结果强烈表明，税务介导的NF-κB激活不需要TAK1和K63连接的NEMO的多泛素化。基于这些结果，我们提出了一种新的税收激活NF-κB的模型。(2)IL-1的高表达参与了肿瘤的恶性进展。我们发现，IL-1刺激导致TRAF6催化的K63连接的TAK1多泛素化，这是TAK1激活所必需的。我们进一步发现，MEKK3是TAK1必需的上游激活剂，TRAF6、MEKK3和TAK1以IL-1刺激依赖的方式形成信号复合体。我们提出了两相的NF-κB激活模型，其中依赖于Tak1的环途径先于不依赖于Tak1的锌途径。(3)筛选出25个可能与肿瘤恶性相关的核转录因子-κB靶基因。(4)6株乳腺癌、肺癌和胃癌细胞系的生长依赖于核因子-kB的激活，其生长方式依赖于IKKα。这一结果表明，非经典途径参与了它们的增殖。

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.