Specificity of the Ubiquitin System in Lymphoid Malignancies

描述（由申请人提供）：核因素-？B (NF - ?B)蛋白质是造血细胞生长、分化和存活的关键。NF-？B基因是由染色体易位、基因融合异常、癌基因表达不当和基因突变引起的，在许多淋巴系统疾病中都发现了B基因，并有助于B淋巴细胞和t淋巴细胞的恶性转化。尽管在患者治疗方面已经取得了进步，但在分子水平上，要实现更有效和更持久的治疗，仍有许多有待了解的地方。通过泛素途径改变蛋白质降解在淋巴系统疾病的发病机制中很常见。我们拟研究Fbxw7在血液病中的作用。Fbxw7 （F-box/WD40重复包含蛋白7）是F-box蛋白家族的成员，作为泛素连接酶，靶向蛋白酶体依赖降解的特定底物。我们的数据显示Fbxw7调节NF-？B通路在细胞特异性环境中的作用。在多发性骨髓瘤细胞中，Fbxw7作为促生存基因通过促进NF-？B抑制剂，Nfkb2 （p100）。在揭示调节p100降解的信号通路的努力中，我们已经确定Tao2是调节Fbxw7-p100相互作用的激酶。在ai1中，我们建议研究Tao-Fbxw7-p100轴的功能作用及其对NF-？B活化在多发性骨髓瘤生存中的作用。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），Fbxw7作为肿瘤抑制基因，抑制NF-？B的活动。在这种情况下，我们发现Fbxw7靶向NF-？B途径，RelA，用于蛋白酶体降解。因此，本应用程序的第二个目标是揭示允许Fbxw7抑制NF-？B活性和阻止T-ALL存活（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aims中，我们建议进行功能性遗传筛选，以鉴定允许多发性骨髓瘤细胞存活的特定泛素连接酶。蛋白酶体抑制剂硼替佐米已被证明是多发性骨髓瘤的有效治疗方法，这使得泛素途径特别有吸引力，为癌症治疗提供了新的工具。总之，这些研究结果将揭示通过泛素系统控制血液病增殖的分子机制，从而为治疗方法的发展开辟新的途径。

DESCRIPTION (provided by applicant): 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 cell. 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.