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: 10477962
• 负责人: Robert Neil Eisenman
• 金额: $ 103.49万
• 依托单位: FRED HUTCHINSON CANCER 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 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10477962
• 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蛋白对于正常的细胞生长和增殖至关重要。但是，当它的正常法规 受到妥协（即放松管制）MYC促进了人类广泛的倡议和发展 癌症。 MYC长期以来一直是转录因子，它与最大蛋白在 为了特别识别DNA。放松管制时，myc-max改变了基因表达程序的结果 在代谢和生长相关的变化中，这反过来支持肿瘤进展。最近的研究表明MYC- Max不单独发挥作用，而是相关的较大转录“网络”的一部分 Tinct，与Max或Max-like蛋白MLX或两者兼而有之的异二聚体的因素。为了理解 并控制MYC在癌症病因中的作用，定义MYC如何依赖和 影响扩展网络。该应用程序建立在我们正在进行的研究的三个广泛方面： 代谢的转录重编程：我们早些时候发现了MLX的关键作用，其异质 二聚体伴侣Mondoa，在几种MYC驱动肿瘤的代谢和生存中。专注于pancre- ATIC腺癌我们将检查涉及MYC的串扰和功能依赖性 它的扩展网络可能被利用以确定新的治疗策略。而且，迈克和 其他网络蛋白是转录因素，我们将确定它们的共享靶基因及其共享基因 对染色质修饰和高阶结构以及基因表达的手术作用。 MACE网络的成员MGA介导的肿瘤抑制：MGA是一个大而不寻常的转录本- 具有两个不同DNA结合结构域的特性因子，其中一个与最大二聚体，结合DNA，是频率 在广泛的肿瘤中，敏锐地受到缺失或突变。但是，关于MGA的知之甚少 致癌功能。我们最近的发现，MGA功能丧失会导致体外细胞运动的改变， 小鼠中的快速肺腺癌形成提供了一种生物系统，以阐明MGA的能力 抑制癌症。我们将在MGA中定义DNA结合必不可少的区域，识别转录复合物 与MGA相关，并评估MGA损失如何导致肿瘤倡议，进展和转移。 驱动MYC致癌性的分子改变：我们引入了与B细胞相关的点突变（T58A） 淋巴瘤和AML，内源性鼠MYC基因的磷光dephodegron中。在这些老鼠中，迈克 - T58a通常受到组织生长或增殖的明显变化。但是我们发现Myc-t58a 小鼠表现出增加的造血祖细胞细胞自我更新和对凋亡的抗性，并发展 长延迟AML或淋巴瘤。我们的数据表明，MYC-T58A突变改变了MYC的关联 具有特定的共调节络合物。我们假设这种改变的结合改变了子的表达 造血过程中MYC靶基因的种群，导致肿瘤引发的细胞产生。我们计划 阐明这些容易发生肿瘤的小鼠中T58A表型的基本分子基础。