Specificity of the Ubiquitin System in Lymphoid Malignancies

项目概要： 核因子B（NF-B）蛋白对造血干细胞的生长、分化和存活起着关键作用。 细胞NF-B基因的失调，由染色体易位，异常基因融合， 癌基因的不适当表达和基因突变，已在许多淋巴疾病中发现， 有助于B-和T-淋巴细胞的恶性转化。虽然已经有所改善， 在患者治疗中，在分子水平上仍有许多有待理解的问题，以实现更有效和 更持久的治疗。通过泛素途径的蛋白质降解的改变通常见于 淋巴疾病的发病机制。在这里，我们建议研究Fbxw 7在血液病中的作用。 Fbxw 7（F-box/WD 40 repeat-containing protein 7）是F-box蛋白家族的成员，其功能为 一种靶向蛋白酶体依赖性降解的特异性底物的泛素连接酶。我们的数据 揭示了Fbxw 7在细胞特异性环境中调节NF-B通路。在多发性骨髓瘤细胞中，Fbxw 7 通过促进NF-B抑制剂Nfkb 2（p100）的降解作为促存活基因发挥作用。的努力中 为了揭示调节p100降解的信号通路，我们已经确定Tao 2是一种激酶， 调节Fbxw 7-p100相互作用。在Aim 1中，我们建议研究Tao-Fbxw 7-p100的功能作用， 轴及其对多发性骨髓瘤生存期中NF-B活化的贡献。相反，在T细胞恶性肿瘤中， 如T-ALL（T细胞急性淋巴细胞白血病），Fbxw 7作为肿瘤抑制基因发挥作用， 抑制NF-B活性。在这种情况下，我们发现Fbxw 7靶向NF-B通路的激活剂， RelA，用于蛋白酶体降解。因此，本申请的第二个目的是揭示本发明的实施例。 允许Fbxw 7抑制NF-B活性并阻止T-ALL存活的分子机制（Aim 2）。最后， 我们将扩大我们的研究泛素系统及其相关性的淋巴疾病的进展。在 目的3我们建议进行功能性遗传筛选，以确定特定的泛素连接酶，使生存 多发性骨髓瘤细胞。蛋白酶体抑制剂硼替佐米已被证明是一种有效的治疗多种 骨髓瘤，使泛素途径特别有吸引力，为癌症治疗提供新的工具。所有 总之，这些研究的结果将揭示控制细胞增殖的分子机制。 通过泛蛋白系统治疗血液病，从而为药物开发开辟了新途径 治疗学

Project summary: The nuclear factor-¿B (NF-¿B) proteins are pivotal for growth, differentiation and survival of hematopoietic cells. Misregulation of NF-¿B genes, caused by chromosomal translocations, aberrant gene fusions, inappropriate expression of oncogenes and gene mutations, has been found in many lymphoid diseases and contributes to the malignant transformation of B- and T-lymphocytes. Although improvements have been made in patient treatment, much remains to be understood at the molecular level to achieve more effective and longer lasting therapies. Alteration of protein degradation through the ubiquitin pathway is commonly found in the pathogenesis of lymphoid diseases. Here we propose to study the role of Fbxw7 in hematologic diseases. Fbxw7 (F-box/WD40 repeat-containing protein 7) is a member of the F-box family of proteins that functions as an ubiquitin ligase enzyme targeting specific substrates for proteasome dependent degradation. Our data have revealed that Fbxw7 regulates the NF-¿B pathway in cell specific context. In multiple myeloma cells, Fbxw7 functions as a pro-survival gene by promoting the degradation of the NF-¿B inhibitor, Nfkb2 (p100). In the effort of revealing the signaling pathways that regulate p100 degradation, we have identified Tao2 as the kinase that regulates the Fbxw7-p100 interaction. In Aim1, we propose to study the functional role of the Tao-Fbxw7-p100 axis and its contribution to NF-¿B activation in multiple myeloma survival. Conversely, in T cell malignancies, such as T-ALL (T-cell acute lymphoblastic leukemia), Fbxw7 functions as a tumor suppressor gene, suppressing NF-¿B activity. In this context, we found that Fbxw7 targets an activator of the NF-¿B pathway, RelA, for proteasomal degradation. Therefore, the second objective of this application is to unravel the molecular mechanisms that allow Fbxw7 to inhibit NF-¿B activity and prevent T-ALL survival (Aim2). Finally, we will broaden our studies on the ubiquitin system and its relevance in lymphoid diseases progression. In Aim3 we propose to perform functional genetic screens to identify specific ubiquitin ligases that allow survival of multiple myeloma cells. A proteasome inhibitor, bortezomib, has proven an effective treatment for multiple myeloma, rendering the ubiquitin pathway particularly appealing for providing new tools for cancer therapy. All together, the results of these studies will shed light into the molecular mechanisms that control proliferation of hematological diseases via the ubiquitin system, thus opening a new avenue for the development of therapeutics.