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: 10601462
• 负责人: Robert Neil Eisenman
• 金额: $ 47.99万
• 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/10601462
• 关键词: MYC; Transcription; Factor; Network; Path

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蛋白对于正常细胞生长和增殖至关重要，但是，当其正常调节时。 Myc 受到损害（即解除管制），可促进广泛的人类疾病的起始和进展 长期以来，人们都知道 Myc 是一种与 Max 蛋白异二聚化的转录因子。 为了特异性识别 DNA，当解除管制时，Myc-Max 会改变基因表达程序。 最近的研究表明，Myc- 与代谢和生长相关的变化反过来支持肿瘤的进展。 Max 并不单独发挥作用，而是一个更大的转录“网络”的一部分，该网络由相关但功能分散的转录“网络”组成。 tinct，与 Max 或 Max 样蛋白 MLX 或两者异二聚化的因子。 并控制 Myc 在癌症病因学中的作用，因此有必要定义 Myc 如何依赖和控制 该应用程序建立在我们正在进行的研究的 3 个广泛方面之上： 新陈代谢的转录重编程：我们之前发现了 Mlx 及其异源性的关键作用 二聚体伙伴 MondoA，在几种 Myc 驱动的肿瘤的代谢和存活中的作用 对于动脉性腺癌，我们将在涉及的背景下检查 Myc 的串扰和功能依赖性 此外，Myc 和它的扩展网络可用于确定新的治疗策略。 其他网络蛋白是转录因子，我们将确定它们共享的靶基因及其共同 对染色质修饰和高级结构以及基因表达的操作影响。 由 Myc 网络成员 Mga 介导的肿瘤抑制：Mga 是一个巨大且不寻常的转录物 - 化因子具有两个不同的 DNA 结合域，其中一个与 Max 形成二聚体，结合 DNA，并且是自由的 经常在多种肿瘤中发生缺失或突变然而，人们对 Mga 知之甚少。 我们最近发现 Mga 功能丧失会导致体外细胞运动性改变， 小鼠肺腺癌的快速形成提供了一个生物系统来阐明 Mga 的能力 我们将定义 Mga 中 DNA 结合所必需的区域，识别转录复合物。 与 Mga 相关，并评估 Mga 的缺失如何导致肿瘤的发生、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，位于内源性鼠 myc 基因的磷酸降解子内，在这些小鼠中，Myc-。 T58A 受到正常调节，组织生长或增殖没有明显变化，但我们发现 myc-T58A。 小鼠表现出增强的造血祖细胞自我更新和抗凋亡能力，并发展 我们的数据表明，Myc-T58A 突变改变了 Myc 的关联。 我们认为改变的结合会改变子的表达。 我们计划在造血过程中增加 Myc 靶基因的数量，从而产生肿瘤起始细胞。 阐明这些易患肿瘤的小鼠中 T58A 表型的潜在分子基础。