GENETIC ANALYSIS OF MYB PROTOONCOGENE FUNCTION

myb基因在进化过程中高度保守。 三百万- 相关基因（c-myb、A-myb和B-myb）已经在哺乳动物中鉴定， 鸟类和两栖动物。 c-myb基因是胎儿发育所必需的 造血作用和c-myb改变形式导致白血病和淋巴瘤 哺乳动物和鸟类。 Myb蛋白是核蛋白，与特定的DNA结合， 序列并调节转录。 然而，关键基因， 位于myb通路的上游和下游仍然未知。 一 果蝇myb相关基因的发现已有十多年， 基本上没有特征。 我们已经证明果蝇Myb DNA结合结构域识别与Myb蛋白相同的DNA序列， 脊椎动物和细胞黏菌盘基网柄菌。 此外，我们最近发现果蝇Myb基因的片段 蛋白质可以在功能上取代脊椎动物V- myb蛋白在致癌转化中的作用。 此外，我们发现， 脊椎动物Myb蛋白与果蝇Myb蛋白同源性较高 比以前认识到的要多。 高度进化的 脊椎动物中其他致癌基因相关途径的保守性， 果蝇和秀丽隐杆线虫让我们相信 myb通路可能是类似保守的。 所以我们现在 我建议使用果蝇中可用的遗传和生化工具， 和c. elegans为了将myb置于遗传途径中。 到 为实现这一目标，我们提出以下具体目标： 1. 明确myb基因表达的调控模式和机制 在果蝇的不同发育阶段; 2. 为了确定果蝇Myb蛋白是否可以作为 组织培养细胞和完整动物中的转录调节因子; 3. 为了创造转基因果蝇， 型和/或突变型Myb引起可评分表型; 4. 使用这些表型来鉴定和排序基因， 抑制Myb功能; 5. 鉴定受果蝇Myb蛋白调控的靶基因; 6. 鉴定和表征myb相关基因的表达， 蛋白质在C.优雅

The myb genes have been highly conserved during evolution. Three myb- related genes (c-myb, A-myb, and B-myb) have been identified in mammals, birds, and amphibians. The c-myb gene is essential for fetal hematopoiesis and altered forms of c-myb cause leukemias and lymphomas in mammals and birds. The Myb proteins are nuclear, bind to specific DNA sequences and regulate transcription. However, the critical genes that lie upstream and downstream in the myb pathway remain unknown. A Drosophila myb-related gene was first identified over ten years ago, but remains largely uncharacterized. We have shown that the Drosophila Myb DNA-binding domain recognizes the same DNA sequence as Myb proteins from vertebrates and from the cellular slime mold Dictyostelium discoideum. Furthermore, we have recently shown that segments of the Drosophila Myb protein can functionally replace homologous segments of the vertebrate v- Myb protein in oncogenic transformation. In addition, we have found that the homology among vertebrate Myb proteins and Drosophila Myb is more extensive than previously appreciated. The high degree of evolutionary conservation of other oncogene-related pathways among vertebrates, Drosophila, and the nematode Caenorhabditis elegans leads us to believe that the myb pathway may be similarly conserved. Therefore, we now propose to use the genetic and biochemical tools available in Drosophila and C. elegans in order to place myb within a genetic pathway. To accomplish this goal, we propose the following specific aims: 1. To determine the pattern and mechanism of regulation of myb expression in Drosophila during various stages of development; 2. To determine if the Drosophila Myb protein can function as a transcriptional regulator in tissue culture cells and in intact animals; 3. To create transgenic Drosophila in which the misexpression of wild type and/or mutant forms of Myb cause scoreable phenotypes; 4. To use these phenotypes to identify and order genes that enhance or suppress Myb function; 5. To identify target genes regulated by the Drosophila Myb protein; and, 6. To identify and characterize the expression of myb-related gene(s) and protein(s) in C. elegans.