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蛋白是细胞正常生长和增殖所必需的。然而，当它的正常监管 Myc是否受到损害(即放松管制)促进了广泛人类的启动和发展 癌症。长期以来，人们一直知道MYC是一种转录因子，它与MAX蛋白在 才能专门识别DNA。当解除管制时，Myc-Max会改变基因表达程序，从而 代谢和生长相关的变化，进而支持肿瘤的进展。最近的研究表明，Myc- MAX并不是单独发挥作用的，而是一个更大的转录网络的一部分，该网络由相关的、但功能上不同的 色泽，与MAX或MAX类蛋白MLX或两者均可异源二聚体的因子。为了理解 并控制Myc在癌症病因学中的作用定义Myc如何依赖于和 影响扩展网络。此应用程序基于我们正在进行的研究的3个主要方面： 新陈代谢的转录重编程：我们早些时候发现了MLX及其异源基因的关键作用。 二聚体伙伴Mondoa，在几个Myc驱动的肿瘤的新陈代谢和生存中。专注于Pancre- ATIC腺癌，我们将在以下背景下检查涉及Myc的串扰和功能依赖 它的扩展网络可以被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，我们将确定它们共同的靶基因和它们的协同作用。 对染色质修饰和高阶结构以及基因表达的操作影响。 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- 转录因子具有两个不同的DNA结合域，其中一个与MAX二聚化，与DNA结合，并与DNA结合。 在广泛的肿瘤中容易发生缺失或突变。然而，人们对MGA的了解很少 致癌功能。我们最新的发现是，MGA功能丧失会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种生物系统来阐明MGA的能力 抑制癌症。我们将定义MGA中DNA结合所必需的区域，识别转录复合体 与MGA相关，并评估MGA缺失如何导致肿瘤的发生、发展和转移。 推动Myc致癌的分子变化：我们引入了一个与B细胞相关的点突变(T58A) 淋巴瘤和急性髓细胞白血病，在内源性小鼠myc基因的磷酸变性内。在这些小鼠中，Myc- T58A被正常调节，组织生长或增殖没有明显变化。然而，我们发现myc-T58A 小鼠表现出造血祖细胞自我更新和抗凋亡能力增强，并发展为 长潜伏期AML或淋巴瘤。我们的数据显示，Myc-T58A突变改变了Myc的关联性 有一个特定的共同监管复合体。我们假设这种改变的结合修改了亚基的表达 在造血过程中Myc靶基因的聚集，导致肿瘤起始细胞的产生。我们计划 目的：阐明T58A表型在这些易患肿瘤的小鼠中的潜在分子基础。