Specificity of the Ubiquitin System in Lymphoid Malignancies

泛素系统在淋巴恶性肿瘤中的特异性

• 批准号: 8795097
• 负责人: Luca Busino
• 金额: $ 24.27万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-27 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8795097
• 关键词: Acute T Cell Leukemia; Address; Affect; Biological; Bortezomib; Candidate Disease Gene; Cell Proliferation; Cells; Chromosomal translocation; Complement Factor B; Complex; DNA damage checkpoint; Data; Differentiation and Growth; Disease; Disease Progression; Enzymes; Event; F Box Domain; Family; Gene Fusion; Gene Mutation; Genes; Genetic Screening; Genetic Transcription; Growth; Half-Life; Hematologic Neoplasms; Hematological Disease; Hematopoietic; Knowledge; Lead; Light; Lymphoid; Malignant - descriptor; Malignant Neoplasms; Malignant lymphoid neoplasm; Molecular; Monitor; Multiple Myeloma; Mutation; Nuclear; Oncogenes; Pathogenesis; Pathway interactions; Patients; Phosphotransferases; Proteasome Inhibitor; Protein Family; Proteins; Regulation; Role; SKP Cullin F-Box Protein Ligases; Signal Pathway; Specificity; Study Subject; System; T-Lymphocyte; Training; Translating; Tumor Suppressor Genes; Ubiquitin; Validation; base; cancer therapy; cell type; circadian pacemaker; design; effective therapy; human disease; in vivo Model; inhibitor/antagonist; member; multicatalytic endopeptidase complex; novel; prevent; protein degradation; protein function; therapeutic development; tool; ubiquitin ligase; ubiquitin-protein ligase

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.

项目概要： 核因子-¿ B (NF-¿B) 蛋白对于造血系统的生长、分化和存活至关重要 NF-¿ 细胞的失调。 B基因，由染色体易位、异常基因融合引起， 癌基因和基因突变的不适当表达，已在许多淋巴疾病和 尽管已经有所改善，但它仍会导致 B 淋巴细胞和 T 淋巴细胞的恶性转化。 在患者治疗中，为了实现更有效和更有效的治疗，在分子水平上还有很多需要了解的地方。 通过泛素途径改变蛋白质降解的情况常见于。 在这里，我们建议研究 Fbxw7 在血液疾病中的作用。 Fbxw7（含 F-box/WD40 重复序列的蛋白 7）是 F-box 蛋白家族的成员，其功能为 我们的数据显示，一种针对蛋白酶体依赖性降解的特定底物的泛素连接酶。 揭示 Fbxw7 调节 NF-¿细胞特定环境中的 B 通路。在多发性骨髓瘤细胞中，Fbxw7。 通过促进 NF-¿ 的降解而发挥促生存基因的作用B 抑制剂，Nfkb2 (p100)。 为了揭示调节 p100 降解的信号通路，我们确定了 Tai2 作为激酶 调节Fbxw7-p100相互作用在Aim1中，我们建议研究Tao-Fbxw7-p100的功能作用。 轴及其对 NF-¿ 的贡献B 激活在多发性骨髓瘤离线、T 细胞恶性肿瘤中的作用。 例如T-ALL（T细胞急性淋巴细胞白血病）、Fbxw7作为抑癌基因， 抑制 NF-¿在这种情况下，我们发现 Fbxw7 的目标是 NF-¿ 的激活剂。 B途径， RelA，用于蛋白酶体降解。因此，该应用的第二个目标是阐明这一点。 Fbxw7 抑制 NF-¿ 的分子机制B 活性并阻止 T-ALL 存活（目标 2）。 我们将扩大对泛素系统及其与淋巴疾病进展的相关性的研究。 Aim3 我们建议进行功能性遗传筛选，以确定允许生存的特定泛素连接酶 蛋白酶体抑制剂硼替佐米已被证明是治疗多发性骨髓瘤细胞的有效方法。 骨髓瘤，使得泛素途径特别有吸引力，可以为癌症治疗提供新工具。 总之，这些研究的结果将揭示控制增殖的分子机制。 通过泛素系统治疗血液病，从而为血液病的发展开辟了新途径 疗法。