Biology of the Myb-MuvB Oncoprotein Tumor Suppressor Protein Complex

Myb-MuvB 癌蛋白肿瘤抑制蛋白复合物的生物学

• 批准号: 8640110
• 负责人: Joseph Steven Lipsick
• 金额: $ 26.66万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8640110
• 关键词: Alleles; Animal Model; Animals; Binding; Biochemical; Biochemical Pathway; Biochemistry; Biological; Biological Assay; Biology; Breast Cancer Treatment; Cancer Etiology; Cancer Patient; Candidate Disease Gene; Cell Cycle; Cell Cycle Regulation; Cell division; Cells; Cellular biology; Chromatin; Chromosomes; Complex; Core Protein; DNA; DNA Binding Domain; Development; Drosophila genus; Drosophila melanogaster; Epigenetic Process; Family; G2 Phase; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Models; Genomics; Goals; Health; Histone Code; Histones; Human; Lead; MYBL2 gene; Maintenance; Malignant Neoplasms; Maps; Mediating; Methods; Mitosis; Molecular; Molecular Chaperones; Mutate; Mutation; N-terminal; Nematoda; Neurons; Nucleosomes; Odorant Receptors; Oncogene Proteins; Other Genetics; Pathway interactions; Phenotype; Play; Property; Protein Family; Proteins; Reader; Receptor Gene; Recombinants; Recruitment Activity; Regulation; Reporter Genes; Resources; Role; Site; Soil; Structure; Study models; System; Tertiary Protein Structure; Testing; Therapeutic; Transcription Repressor/Corepressor; Tumor Suppressor Genes; Tumor Suppressor Proteins; Variant; Vertebrates; Work; cell type; chromatin modification; design; in vivo; leukemia; leukemia/lymphoma; loss of function; malignant breast neoplasm; mutant; myb Genes; outcome forecast; prevent; protein complex; small molecule; tool; v-myb Genes

DESCRIPTION (provided by applicant): Cancer is caused by mutations (alterations) in oncogenes and tumor suppressor genes. Much of what we know about the function of cancer-causing genes comes from studies of genetic model organisms like fruit flies and soil nematodes. This project focuses on the Myb oncoprotein and its interactions with a four-protein tumor suppressor complex called the MuvB core. The fruit fly is an excellent model for these studies because it has only one Myb gene, whereas vertebrate animals including humans have three related Myb genes. In particular, the human B-Myb gene that is associated with poor prognosis in human breast cancer is structurally similar to and can functionally replace the Myb gene of fruit flies. Previous work has shown that the MuvB tumor suppressor proteins prevent the expression of genes that promote cell division. The Myb protein directly interacts with the MuvB proteins, thereby permitting the expression of the genes that MuvB inhibits. A major goal of this proposal is to understand in molecular detail the mechanism by which Myb and MuvB regulate gene expression. The tools of genetics, biochemistry, and cell biology will be used to identify the changes in chromatin (DNA and associated proteins) that occur in the presence of Myb and MuvB. Another major goal is to understand exactly how the Myb and MuvB proteins interact with and regulate one another. A relatively small portion of the Myb protein is sufficient to interact with the MuvB proteins and inhibit their function. A better understanding of the precise structures that mediate this interaction may lead to the development of new small molecules that will be useful in the treatment of breast cancers with increased levels of B-Myb.

描述（由申请人提供）：癌症是由癌基因和肿瘤抑制基因的突变（改变）引起的。我们对致癌基因功能的大部分了解都来自对果蝇和土壤线虫等遗传模式生物的研究。该项目的重点是Myb癌蛋白及其与称为MuvB核心的四蛋白肿瘤抑制复合物的相互作用。果蝇是这些研究的一个很好的模型，因为它只有一个Myb基因，而包括人类在内的脊椎动物有三个相关的Myb基因。特别是，与人乳腺癌预后不良相关的人B-Myb基因在结构上类似于果蝇的Myb基因，并且可以在功能上取代果蝇的Myb基因。 先前的工作表明MuvB肿瘤抑制蛋白可以阻止促进细胞分裂的基因的表达。Myb蛋白直接与MuvB蛋白相互作用，从而允许MuvB抑制的基因表达。该提案的一个主要目标是在分子上详细了解Myb和MuvB调节基因表达的机制。遗传学、生物化学和细胞生物学的工具将用于鉴定在Myb和MuvB存在下发生的染色质（DNA和相关蛋白质）的变化。另一个主要目标是准确了解Myb和MuvB蛋白如何相互作用和相互调节。一个相对较小的Myb蛋白就足够了 与MuvB蛋白相互作用并抑制其功能。更好地了解介导这种相互作用的精确结构可能会导致新的小分子的开发，这些小分子将用于治疗B-Myb水平升高的乳腺癌。