Myc, WDR5, and Cancer

随着技术的扩展和实施这些技术所需的专业知识，它已经成为 主要调查人员有必要依赖具有更有意义的科学地位的科学家，以便 保持科学产出和连续性。为了促进这些研究专家的发展，NCI 最近建立了一种新的资助机制，R50，用于支付那些不想要的职业科学家的工资 成为独立的调查人员，但更愿意在现有的NCI资助的情况下进行研究 程序。 作为研究专家，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 MYC。MYC癌基因编码一系列相关的转录因子，这些转录因子在 据估计，美国每年有10万人死于与癌症有关的疾病。MYC 蛋白质的致癌性来自于它们结合染色质和调节转录的能力 数以千计的基因控制细胞生长、细胞周期进程、血管生成、转移、基因组 不稳定和新陈代谢重新编程。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与染色质的确切结合程度 在染色质的背景下招募到其靶基因。 因为MYC中心部分的几个基序在整个进化过程中高度保守 推测它们对MYC的功能可能很重要。为了检验这一假设，我设计了一种策略 整合双杂交和蛋白质组筛选人c-myc基因中心部分并鉴定WDR5为 一种真正的MYC相互作用蛋白。WDR5是几种表观遗传‘作家’的核心成分 复合体，包括MLL1甲基转移酶，其典型作用是通过 将MLL1桥接到其共激活子上。我证明了WDR5对于靶向myc的靶基因是必不可少的。 这种相互作用对于MYC诱导的肿瘤形成和诱导多能性的形成是必要的 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，该模型 假设MYC转录复合体与靶基因染色质的广泛关联涉及两个 关键的相互作用集：一组与DNA相互作用，另一组与预先结合的WDR5和邻近的WDR5相互作用(由 NCI-1R01CA200709)。我们还假设，并与范德比尔特的Fesik小组合作，我们 可以识别阻止WDR5参与MLL1作为癌症治疗手段的小分子(资助 由NCI实验治疗计划分包合同编号29XS129TO27)。这笔赠款的目的是 支付我在Tansey实验室的这两个研究项目的工资。

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.