Biology of the Myb-MuvB Oncoprotein Tumor Suppressor Protein Complex

描述(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来自对果蝇和土壤线虫等遗传模式生物的研究。这个项目的重点是Myb癌蛋白及其与称为MuvB核心的四蛋白肿瘤抑制复合体的相互作用。果蝇是这些研究的绝佳模型，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，与人类乳腺癌预后不良相关的人B-Myb基因在结构上与果蝇的Myb基因相似，并且在功能上可以取代果蝇的Myb基因。之前的工作表明，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抑制的基因的表达。这项建议的一个主要目标是从分子细节上了解Myb和MuvB调控基因表达的机制。遗传学、生物化学和细胞生物学的工具将被用来确定在Myb和MuvB存在的情况下染色质(DNA和相关蛋白质)发生的变化。另一个主要目标是确切地了解Myb和MuvB蛋白是如何相互作用和调节的。Myb蛋白的相对较小部分就足够了 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，这些小分子将有助于B-Myb水平升高的乳腺癌的治疗。

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.