Specificity of the Ubiquitin System in Lymphoid Malignancies

项目总结： 核因子B(NFB)蛋白对造血细胞的生长、分化和存活起关键作用 细胞。核因子-B基因调控失调，由染色体易位、基因融合异常、 癌基因和基因突变的不适当表达，在许多淋巴系统疾病和 有助于B和T淋巴细胞的恶性转化。尽管已经有了一些改进 在患者的治疗中，要实现更有效和更有效的治疗，在分子水平上仍有许多需要了解的地方 更持久的疗法。泛素途径引起的蛋白质降解改变通常见于 淋巴系疾病的发病机制。在这里，我们建议研究Fbxw7在血液病中的作用。 Fbxw7(F-box/WD40重复蛋白7)是F-box蛋白家族中的一员，其功能是 一种针对特定底物的泛素连接酶，用于蛋白酶体依赖的降解。我们的数据显示 揭示了Fbxw7在细胞特异性背景下调节核因子-βB途径。在多发性骨髓瘤细胞中，Fbxw7 通过促进核因子-B抑制物NFKB2的降解，发挥促生存基因的作用(P100)。在努力中 在揭示调节P100降解的信号通路方面，我们已经确定了taw2是一种 调节Fbxw7-P100的相互作用。在Aim1中，我们建议研究Tao-Fbxw7-P100的功能作用 AXIS及其在多发性骨髓瘤生存中对核因子-B激活的贡献。相反，在T细胞恶性肿瘤中， 例如T-ALL(T细胞急性淋巴细胞性白血病)、Fbxw7作为肿瘤抑制基因， 抑制核因子-βB活性。在此背景下，我们发现Fbxw7靶向于核因子-B途径的激活物， Rela，用于蛋白酶体的降解。因此，此应用程序的第二个目标是解开 Fbxw7抑制核因子-βB活性和阻止T-ALL存活的分子机制(AIM2)。最后， 我们将扩大我们对泛素系统及其在淋巴疾病进展中的相关性的研究。在……里面 Aim3我们建议进行功能性遗传筛选，以确定允许存活的特定泛素连接酶 多发性骨髓瘤细胞。蛋白酶体抑制剂Bortezomib已被证明是治疗多发性硬化症的有效药物。 骨髓瘤，使得泛素途径特别吸引人，为癌症治疗提供新的工具。全 总而言之，这些研究的结果将有助于揭示控制细胞增殖的分子机制。 通过泛素系统治疗血液病，从而开辟了一条新的发展途径 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.