TRANSCRIPTIONAL REGULATORS IN CANCER

本计划项目申请的目标是调查 发育中断和癌症之间的联系。 我们将使用 综合多生物体方法，特别侧重于 调节正常发育的转录因子， 与肿瘤发生有关 大量研究表明 导致癌症的基因似乎是通过四种一般性的 机制：（1）异常的信号转导导致不适当的 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的失败 （3）DNA修复异常（mutS和mutL 同源物）;和（4）转录因子的失调， 在分化过程中调节细胞特性（HOX，HRX，PBX，bmi-1，myb， maf）。 后一种机制目前还知之甚少， 本提案的重点。 因为许多调节发育和生长的转录因子 也导致癌症在进化过程中高度保守， 有机会利用几个国家的互补优势， 实验系统和调查人员，以解开 细胞身份的不适当确定与 肿瘤发生 因此，我们建议研究几个这样的基因家族， 采用纵向一体化的方法， 实验室小鼠的“基因敲除”遗传学和人类相关性; 基因工具箱和广泛的知识，发展，细胞周期， 调节和细胞遗传学;以及近 细胞谱系，遗传图谱和物理基因组的完整知识 秀丽隐杆线虫的地图。

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.