Effect of the Ras oncogene on genomic stability

人类癌症，特别是实体瘤的标志是基因组不稳定性。通过Ras癌基因的合成致死筛选，我们发现Ras突变癌细胞表现出增加的有丝分裂应激，并且更依赖于许多有丝分裂基因的适当功能。目的研究Ras突变对有丝分裂和染色体分离的影响。了解突变型Ras影响有丝分裂机制的机制。我们将使用KRAS WT和突变型等基因细胞以及依赖或不依赖KRAS的癌细胞系来研究它们对有丝分裂进程扰动的反应。 2011财年完成在过去的一年中，我们鉴定了一种新基因，该基因1）显示Ras突变的合成致死性，2）是有丝分裂中染色体聚集所必需的。该基因的表达与侵袭性结直肠癌（CRC）和具有KRAS突变的CRC患者的不良预后相关。我们目前正在研究该基因调节有丝分裂和基因组稳定性的机制。

BACKGROUND A hallmark of human cancer, particularly solid tumor, is genomic instability. Through a synthetic lethal screen with the Ras oncogene we have found that Ras mutant cancer cells exhibit increase mitotic stress and are more dependent on the proper function of a number of mitotic genes. PURPOSE To study the effect of Ras mutation in mitosis and in chromosomal segregation. To understand the mechanisms by which mutant Ras affects the mitotic machinery. SIGNIFICANT MATERIALS AND METHODS We will use KRAS WT and mutant isogenic cells as well as cancer cell lines that are either dependent or independent of KRAS to investigate their response to perturbation of mitotic progression. FY2011 ACCOMPLISHMENT In the past year we have identified a novel gene that 1) show synthetic lethality with Ras mutation and 2) is required for chromosome congression in mitosis. The expression of this gene is associated with aggressive colorectal cancer (CRC) and poor prognosis in CRC patients with KRAS mutations. We are currently invstigating the mechanisms by which this gene regulates mitosis and genomic stability.