The MYC Transcription Factor Network and the Path to Cancer

MYC 转录因子网络和癌症之路

• 批准号: 10228620
• 负责人: Robert Neil Eisenman
• 金额: $ 57.61万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10228620
• 关键词: Apoptosis; Automobile Driving; B-Cell Lymphomas; Binding; Cancer Etiology; Cell Proliferation; Cells; Complex; DNA; DNA Binding; DNA Binding Domain; Data; Dependence; Event; Gene Expression; Genes; Genetic Transcription; Growth; Hematopoiesis; Hematopoietic stem cells; Heterodimerization; Higher Order Chromatin Structure; Human; In Vitro; Lead; Lung Adenocarcinoma; Lymphoma; MAX gene; MYC Family Protein; MYC gene; Malignant Neoplasms; Mediating; Metabolic; Metabolism; Molecular; Mus; Mutation; Neoplasm Metastasis; Neoplasms; Normal Cell; Oncogenic; Pancreatic Adenocarcinoma; Phenotype; Point Mutation; Population; Production; Proteins; Proto-Oncogene Proteins c-myc; Public Health; Regulation; Research; Resistance; Role; Tumor Suppression; biological systems; cancer therapy; cell growth; cell motility; chromatin modification; dimer; loss of function; member; novel strategies; novel therapeutic intervention; programs; self-renewal; transcription factor; transcriptional reprogramming; tumor; tumor initiation; tumor progression

Myc proteins are essential for normal cellular growth and proliferation. However, when its normal regulation is compromised (i.e. deregulated) Myc promotes initiation and progression of a broad spectrum of human cancers. Myc has been long known to be a transcription factor that heterodimerizes with the Max protein in order to specifically recognize DNA. When deregulated, Myc-Max alters gene expression programs resulting in metabolic and growth related changes that in turn support tumor progression. Recent studies show Myc- Max does not function alone, but is part of a larger transcriptional “network” of related, yet functionally dis- tinct, factors that heterodimerize with either Max or the Max-like protein MLX, or both. In order to understand and control Myc's role in the etiology of cancer it will be essential to define how Myc both depends on and influences the extended network. This application builds on 3 broad aspects of our ongoing studies: Transcriptional reprogramming of metabolism: We had earlier uncovered a critical role for Mlx, and its hetero- dimeric partner MondoA, in the metabolism and survival of several Myc-driven tumors. Focusing on pancre- atic adenocarcinoma we will examine cross-talk and functional dependencies involving Myc in the context of its extended network that may be exploited to identify new therapeutic strategies. Moreover, Myc and the other network proteins are transcription factors and we will determine their shared target genes and their co- operative effects on chromatin modifications and higher order structure as well as gene expression. Tumor suppression mediated by Mga, a member of the Myc Network: Mga is a large and unusual transcrip- tion factor with two distinct DNA binding domains, one of which dimerizes with Max, binds DNA, and is fre- quently subject to deletion or mutation in a wide range of neoplasms. However, little is known about Mga's oncogenic functions. Our very recent findings that Mga loss of function results in altered cell motility in vitro, and rapid lung adenocarcinoma formation in mice provide a biological system to elucidate Mga's capacity to suppress cancer. We will define regions in Mga essential for DNA binding, identify transcriptional complexes associated with Mga, and assess how loss of Mga leads to tumor initiation, progression and metastasis. Molecular alterations driving Myc oncogenicity: we introduced a point mutation (T58A), associated with B cell lymphomas and AML, within the phosphodegron of the endogenous murine myc gene. In these mice, Myc- T58A is regulated normally with no overt changes in tissue growth or proliferation. Yet we find that myc-T58A mice display increased hematopoietic progenitor cell self-renewal and resistance to apoptosis, and develop long-latency AML or lymphoma. Our data show that the Myc-T58A mutation alters the association of Myc with a specific co-regulatory complex. We hypothesize that this altered binding modifies expression of a sub- population of Myc target genes during hematopoiesis, resulting in production of tumor initiating cells. We plan to elucidate the underlying molecular basis for the T58A phenotype in these tumor-prone mice.

Myc蛋白是正常细胞生长和增殖所必需的。然而，当其正常调节时