Myc, WDR5, and Cancer

Myc、WDR5 和癌症

• 批准号: 9567939
• 负责人: LANCE R THOMAS
• 金额: $ 12.5万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-20 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9567939
• 关键词: Binding; Cell Cycle Progression; Cessation of life; Chromatin; Collaborations; Complex; DNA; Drug Targeting; Epigenetic Process; Evolution; Family; Funding; Funding Mechanisms; Gene Targeting; Genes; Genetic Transcription; Genomic Instability; Grant; Human; Investigational Therapies; Laboratories; MLL gene; MYC Family Protein; MYC gene; Malignant Neoplasms; Metabolic; Methyltransferase; Mitotic Cell Cycle; Modeling; Modification; Neoplasm Metastasis; Oncogenic; Output; Positioning Attribute; Principal Investigator; Proteins; Proteomics; Research; Research Personnel; Role; Scientist; Seminal; Specialist; Technology; Testing; Validation; Wages; Work; angiogenesis; base; c-myc Genes; cancer therapy; career; design; drug discovery; experience; gene interaction; induced pluripotent stem cell; novel; overexpression; prevent; programs; recruit; research and development; screening; skills; small molecule; stem; transcription factor; tumor; yeast two hybrid system

With the expansion in technologies and the required expertise to implement them, it has become necessary for principal investigators to rely on scientists with a more permeant scientific position in order to maintain scientific output and continuity. To promote the development of these research specialists, the NCI recently established a new funding mechanism, the R50, to pay the salary of career scientists who do not want to become independent investigators, but rather want to pursue research within an existing NCI funded program. As a research specialist, I will actively participate in two separate but related research programs in the Tansey laboratory, both of which stem from my recent work that defined a function for the central portion of MYC. The MYC oncogenes encode a family of related transcription factors that are overexpressed in the majority of cancers and contribute to an estimated 100,000 cancer-related deaths in the USA every year. MYC proteins derive their oncogenicity from their ability to bind chromatin and to modulate the transcription of thousands of genes controlling cell growth, cell cycle progression, angiogenesis, metastasis, genomic instability, and metabolic reprograming. While it has been demonstrate that certain epigenetic modifications are a prerequisite for MYC binding to chromatin, a long standing issue has been determining how exactly MYC is recruited to its target genes within the context of chromatin. Because several motifs within the central portion of MYC are highly conserved throughout evolution I reasoned they might be important for MYC function. To test this hypothesis, I designed a strategy that integrated two-hybrid and proteomic screening of the central portion of human c-MYC and identified WDR5 as a bonafide MYC interacting protein. WDR5 functions as a central component of several epigenetic `writer' complexes, including the MLL1 methyltransferase where its canonical role is to stimulate enzymatic activity by bridging MLL1 to its co-activators. I demonstrated that WDR5 is essential for targeting MYC to its target genes and that this interaction is necessary for MYC induced tumor formation and the genesis of induced pluripotent stem cells. Based on these seminal findings, we propose to test our model of Facilitated Recruitment, which posits that widespread association of MYC transcriptional complexes with target gene chromatin involves two critical sets of interactions: one with DNA and another with pre-bound and proximal WDR5 (to be funded by the NCI - 1R01CA200709). We also hypothesize, and in collaboration with the Fesik group at Vanderbilt, that we can identify small molecules that prevent WDR5 from engaging MLL1 as a means of cancer therapy (Funded by NCI Experimental Therapeutics Program Subcontract No. 29XS129TO27). The purpose of this grant is to cover my salary for these two research programs in the Tansey laboratory.

随着技术的发展和实施这些技术所需的专业知识， 主要研究人员必须依靠具有更深入的科学立场的科学家， 保持科学产出和连续性。为了促进这些研究专家的发展，NCI 最近建立了一个新的资助机制，R50，以支付职业科学家的工资， 成为独立的研究者，而是想在现有的NCI资助的研究中进行研究。 程序. 作为一名研究专家，我将积极参与两个独立但相关的研究项目， Tansey实验室，这两个都源于我最近的工作，定义了一个函数的中心部分， MYC。MYC癌基因编码一个家族的相关转录因子，这些转录因子在肿瘤细胞中过表达。 大多数癌症，并导致美国每年约100，000例癌症相关死亡。Myc 蛋白质的致瘤性来源于它们结合染色质和调节 成千上万的基因控制细胞生长、细胞周期进程、血管生成、转移、基因组 不稳定性和代谢重编程。虽然已经证明某些表观遗传修饰是 作为MYC与染色质结合的先决条件，一个长期存在的问题是确定MYC是如何与染色质结合的。 在染色质的背景下招募到其靶基因。 由于MYC中心部分的几个基序在整个进化过程中高度保守， 它们可能对MYC的功能很重要。为了验证这个假设，我设计了一个策略， 整合了人类c-MYC中心部分的双杂交和蛋白质组学筛选，并将WDR 5鉴定为 一种真正的MYC相互作用蛋白。WDR 5作为几个表观遗传“作家”的核心组成部分发挥作用。 复合物，包括MLL 1甲基转移酶，其中其典型作用是刺激酶活性， 将MLL 1与其共激活剂桥接。我证明了WDR 5对于将MYC靶向其靶基因至关重要 并且这种相互作用对于MYC诱导的肿瘤形成和诱导的多能干细胞的发生是必需的。 干细胞基于这些开创性的发现，我们建议测试我们的促进招聘模型， 假设MYC转录复合物与靶基因染色质的广泛关联涉及两个方面， 关键的相互作用集：一个与DNA，另一个与预结合和近端WDR 5（由 NCI - 1R01CA200709）。我们还与范德比尔特的Fesik小组合作假设， 可以识别阻止WDR 5与MLL 1结合的小分子，作为癌症治疗的一种手段（资助 由NCI实验治疗计划分包合同号29 XS 129 T027）。该补助金的目的是 支付我在坦西实验室的两个研究项目的薪水