TRANSCRIPTIONAL REGULATORS IN CANCER

本计划项目申请的目标是调查 发育受阻与癌症之间的联系。我们将使用 综合多组织方法，特别侧重于 调节正常发育的转录因子，以及 与肿瘤的发生有关。一大批研究表明 致癌基因似乎由四种普通基因操作 机制：(1)信号转导异常导致不适当 细胞生长(癌基因，如sis，erbB，src，ras，nf-1，raf，jun，fos， 和myc)；(2)细胞周期停滞和程序性细胞死亡失败 途径(bcl2、p53、Rb、p16)；(3)异常DNA修复(MutS和MutL 同源基因)；以及(4)转录因子的错误调控，这些转录因子似乎 调节分化过程中的细胞特性(HOX、HRX、PBX、BMI-1、MYB、 MAF)。后一种机制目前知之甚少，是 这项提案的重点。 因为许多调节发育的转录因子和 也会导致癌症在进化过程中高度保守，有一种 有机会利用几家公司的优势互补 实验系统和调查人员，以解开 不恰当地确定细胞身份与 致癌作用。因此，我们建议研究几个这样的基因家族 使用垂直集成的方法并行，该方法将采用： “敲除”基因和与人类有关的实验室小鼠； 遗传工具箱和丰富的发育、细胞周期知识 果蝇的调控和细胞遗传学；以及近 完整的细胞谱系、遗传图谱和物理基因组知识 秀丽隐杆线虫地图。

The goal of this program project application is to investigate the connection between disrupted development and cancer. We will use an integrated multi-organismal approach, with a specific focus on transcription factors that regulate normal development and that have also been implicated in oncogenesis. A large body of research has now shown that the genes that cause cancer appear to operate by four general mechanisms: (1) aberrant signal transduction resulting in inappropriate cell growth (oncogenes such as sis, erbB, src, ras, NF-1, raf, jun, fos, and myc); (2) failure of cell cycle arrest and programmed cell death pathways (bcl2, p53, Rb, p16); (3) aberrant DNA repair (mutS and mutL homologs); and (4) misregulation of transcription factors which appear to regulate cell identity during differentiation (HOX, HRX, PBX, bmi-1, myb, maf). The latter mechanism is poorly understood at present and is the focus of this proposal. Because many of the transcription factors which regulate development and also cause cancer have been highly conserved during evolution, there is an opportunity to take advantage of the complementary strengths of several experimental-systems and investigators in order to unravel the relationship between inappropriate determination of cell identity and oncogenesis. We therefore propose to study several such gene families in parallel using a vertically integrated approach which will employ: the "knock-out" genetics and human-relatedness of the laboratory mouse; the genetic toolbox and extensive knowledge of development, cell cycle regulation, and cytogenetics in Drosophila melanogaster; and the nearly complete knowledge of the cell lineage, genetic map, and physical genome map of Caenorhabditis elegans.