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: 9762884
• 负责人: Robert Neil Eisenman
• 金额: $ 102.43万
• 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 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9762884
• 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 Initiators; 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; 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 受损（即失调）Myc促进广谱人类肿瘤的启动和进展。 癌的Myc是一种转录因子，它与Max蛋白异源二聚体化， 来识别DNA。当解除调控时，Myc-Max改变基因表达程序， 代谢和生长相关的变化，反过来又支持肿瘤的进展。最近的研究表明，Myc- 马克斯并不单独发挥作用，而是一个更大的相关转录“网络”的一部分，但功能上不同。 着色，与Max或Max样蛋白MLX或两者异二聚化的因子。为了解 和控制Myc在癌症病因学中的作用，确定Myc如何依赖于 影响了扩展的网络。该应用程序建立在我们正在进行的研究的3个广泛方面： 代谢的转录重编程：我们早些时候已经发现了Mlx的关键作用，它的异质性， 二聚体伴侣MondoA在几种Myc驱动的肿瘤的代谢和存活中的作用。专注于pancre- 我们将研究Myc在腺癌中的相互作用和功能依赖性， 它的扩展网络可以用来确定新的治疗策略。此外，Myc和 其他网络蛋白是转录因子，我们将确定它们共享的靶基因和它们的协同作用。 对染色质修饰和更高级结构以及基因表达的作用。 由Myc网络成员Mga介导的肿瘤抑制：Mga是一种大而不寻常的转录本， 有两个不同的DNA结合域，其中一个与马克斯二聚化，结合DNA，是自由的， 在广泛的肿瘤中经常发生缺失或突变。然而，人们对Mga的了解甚少。 致癌功能我们最近的研究发现，Mga功能丧失导致体外细胞运动性改变， 和小鼠肺腺癌的快速形成提供了一个生物学系统，以阐明Mga的能力， 抑制癌症。我们将确定Mga中对DNA结合至关重要的区域， 与Mga相关，并评估Mga的丢失如何导致肿瘤发生、进展和转移。 驱动Myc致癌性的分子改变：我们引入了一个点突变（T58 A），与B细胞相关 淋巴瘤和AML，在内源性鼠myc基因的磷酸降解决定子内。在这些小鼠中，Myc- T58 A正常调节，组织生长或增殖无明显变化。但我们发现myc-T58 A 小鼠表现出增强的造血祖细胞自我更新和对凋亡的抗性， 长潜伏期AML或淋巴瘤。我们的数据显示Myc-T58 A突变改变了Myc 一个特定的协同调节复合体我们假设这种改变的结合改变了一个亚细胞的表达， 在造血过程中Myc靶基因的群体，导致肿瘤起始细胞的产生。我们计划 阐明这些肿瘤易感小鼠中T58 A表型的潜在分子基础。