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Myc, WDR5, and Cancer

Myc、WDR5 和癌症

基本信息

批准号：
9766085
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
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-20 至 2020-08-23
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9766085
关键词：
Binding Cell Cycle Progression Cessation of life Chromatin Collaborations Complex DNA Drug Targeting Epigenetic Process Evolution Family Funding Funding Mechanisms 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

项目摘要

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.

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