Regulation of cell growth and proliferation by Myc

Myc 对细胞生长和增殖的调节

• 批准号: 7781554
• 负责人: Robert Neil Eisenman
• 金额: $ 59.84万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 1977
• 资助国家: 美国
• 起止时间: 1977-02-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7781554
• 关键词: Acetylation; Affect; Amino Acid Sequence; Applications Grants; Binding; Binding Sites; Biological; C-terminal; Calcium; Calpain; Cell Density; Cell physiology; Cessation of life; Chromatin; Chromatin Structure; Complex; Data; Detection; Development; Diagnosis; Dimerization; Embryo; Etiology; Event; Family; Gene Expression; Gene Targeting; Genes; Genome; Genomics; Goals; Grant; Histones; Human; Knowledge; Life; Link; Location; MYC Family Genes; Malignant Neoplasms; Mediating; MicroRNAs; Molecular; Molecular Genetics; Mus; Mutate; N-terminal; Nature; Nuclear; Pathway interactions; Peptide Hydrolases; Peptide Sequence Determination; Polycomb; Property; Proteins; Proto-Oncogenes; Recruitment Activity; Regulation; Repression; Role; Sequence-Specific DNA Binding Protein; Signal Transduction; Site; Stem cells; Testing; Tubulin; base; c-myc Genes; cancer type; cell behavior; cell growth; cell growth regulation; cell type; embryonic stem cell; extracellular; genetic analysis; histone modification; member; novel; pluripotency; promoter; protein complex; protein function; public health relevance; research study; response; self-renewal; stem; tumor; tumorigenesis

DESCRIPTION (provided by applicant): This grant application is focused on the molecular functions of the proteins encoded by the myc-protooncogene family. Myc proteins are widely expressed during vertebrate development where they regulate cell growth, proliferation, death, and differentiation in response to diverse extracellular signals. Importantly, deregulation of Myc expression is strongly linked to the etiology of many different types of cancers. Myc proteins are sequence-specific DNA binding proteins known to function as part of a transcriptional regulatory network that activates and represses expression of hundreds of target genes. This is accomplished in part by Myc's ability to recruit higher order complexes, several of which act to modify histones and alter chromatin structure. Myc may also possess functions separable from its transcriptional activities. A major goal of this grant is to elucidate in detail the connection between Myc's molecular functions and its biological effects on cell behavior. Aims 1 and 2 explore the mechanisms underlying Myc's roles in pluripotency and differentiation and are based on our preliminary analyses of genomic binding by Myc in murine embryonic stem (ES) cells. In Aim 1 we extend our study of microRNAs induced by c-Myc in ES cells and test the hypothesis that these miRNAs comprise a Myc-regulated pathway that suppresses differentiation. We will determine whether the miRNA-encoding genes are directly regulated by Myc, and employ genetic analysis to define the events in differentiation affected by the miRNAs and their gene targets. We will also identify additional Myc-regulated miRNAs in stem cells. Aim 2 expands on other functional classes of Myc-regulated genes in ES cells. These include genes encoding chromatin modifying factors and as well as genes that are associated with Polycomb repression complexes (PcG). We propose to determine whether Myc regulates PcG function in ES cells and further examine the effects of (i) modulating Myc levels, and (ii) induction of differentiation, on PcG binding, histone modification, and gene expression for a subset of Myc target and other ES cell genes. Aim 3 is focused on a novel form of the Myc protein ("Myc-nick") that we identified as a cytoplasmic N-terminal cleavage product of Myc generated by calcium-dependent calpain proteases. Myc-nick lacks a Max dimerization domain and nuclear localization sequences. Our preliminary data suggest that Myc-nick binds to and mediates acetylation of tubulin and promotes differentiation. We propose to characterize the binding of Myc-nick to tubulin, determine the nature of its recruited complexes, and use molecular and genetic approaches to define its role in terminal differentiation. Because many tumors are altered in the capacity to differentiate, delineating the functions of Myc in the context of differentiation is likely to be important in understanding Myc's role in oncogenesis. PUBLIC HEALTH RELEVANCE: The focus of this application is on a group of genes (the myc family) that regulate several of the most fundamental properties of living cells: growth, division, death and differentiation. Importantly, myc genes are mutated and deregulated in a very wide range of human cancers. Detailed knowledge of the molecular functions of myc will be critical for detection, diagnosis and treatment of human cancers.

描述（由申请人提供）：此赠款应用集中在Myc-Protooncogen家族编码的蛋白质的分子功能上。 MYC蛋白在脊椎动物发育过程中广泛表达，它们会调节细胞生长，增殖，死亡和分化，以响应各种细胞外信号。重要的是，对MYC表达的放松管制与许多不同类型的癌症的病因密切相关。 MYC蛋白是序列特异性DNA结合蛋白，称为转录调节网络的一部分，该网络激活和压抑数百个靶基因的表达。这部分是由MYC募集高阶复合物的能力来完成的，其中几种可以修改组蛋白并改变染色质结构。 MYC可能还具有与其转录活动可分开的功能。该赠款的主要目标是详细阐明MYC的分子功能与其对细胞行为的生物学作用之间的联系。目标1和2探讨了MYC在多能性和分化中作用的机制，并基于我们对MYC在鼠类胚胎茎（ES）细胞中基因组结合的初步分析。在AIM 1中，我们扩展了C-Myc在ES细胞中诱导的microRNA的研究，并检验了这些miRNA构成抑制分化的MYC调节途径的假设。我们将确定miRNA编码基因是否受到MYC的直接调节，并采用遗传分析来定义受miRNA及其基因靶标影响的分化事件。我们还将确定干细胞中其他由MYC调节的miRNA。 AIM 2扩展了ES细胞中MYC调节基因的其他功能类别。这些包括编码染色质修饰因子以及与多康布抑制复合物（PCG）相关的基因。我们建议确定MYC是否调节ES细胞中的PCG功能，并进一步检查（i）调节MYC水平的影响，以及（ii）诱导分化，对MYC靶标和其他ES细胞基因的子集对PCG结合，组蛋白修饰和基因表达的诱导。 AIM 3专注于我们确定为由钙依赖性的钙蛋白酶蛋白酶产生的MYC的细胞质N末端裂解产物的新型MYC蛋白（Myc-nick）。 Myc-Nick缺乏最大二聚域和核定位序列。我们的初步数据表明，Myc-Nick与微管蛋白的乙酰化结合并介导并促进分化。我们建议表征Myc-Nick与微管蛋白的结合，确定其招募的复合物的性质，并使用分子和遗传方法来定义其在终端分化中的作用。因为许多肿瘤的分化能力发生了变化，因此在分化的背景下描述了MYC的功能对于理解MYC在肿瘤发生中的作用可能很重要。 公共卫生相关性：该应用的重点放在一组基因（MYC家族）上，这些基因（MYC家族）调节了活细胞的几种最基本特性：生长，分裂，死亡和分化。重要的是，MYC基因在非常广泛的人类癌症中被突变和放松。详细了解MYC的分子功能对于人类癌症的检测，诊断和治疗至关重要。