Transforming genes of avian sarcoma viruses

描述（由申请人提供）：锚定独立生长，逃避 接触或细胞密度依赖性生长抑制。增强的迁移和 侵袭活性是体外最重要的特性之一， 转化细胞它们与癌症的特征密切相关 体内细胞参与调节这些的分子信号通路 已经通过使用禽肉瘤研究了转化细胞的性质， 病毒UR2，其编码称为Ros的截短受体酪氨酸激酶，和 其功能丧失的突变体，以及新发现的Ros下游 名为Vav3的效应器。结果表明，PI3激酶和RhoGT3蛋白表达上调。 信号通路在Ros和Vav诱导的 锚定非依赖性生长，摆脱接触抑制和增强 运动性和侵袭性。这项建议的目的是进一步剖析和 鉴定P13激酶和RhoGTPases的下游信号通路 这是重要的，在调节锚定独立的增长，逃避 接触抑制，以及成纤维细胞和上皮细胞的运动和侵袭 细胞此外，新的基因和途径对这些转化很重要， 物业将进行探索。 具体目标是： 1.阐明锚定非依赖性生长的重要分子信号传导 信元 2.阐明调控细胞运动和侵袭的分子信号。 3.探索参与调节细胞运动的新基因和蛋白质， 入侵 4.为了阐明逃避接触抑制的分子基础， 增长 诱导型Ros和Vav癌基因沿着各种组成性激活和 P13激酶和Rho GTPases信号分子的显性失活突变体 将用于剖析转化成纤维细胞中的信号通路， 上皮细胞微阵列和蛋白质组学分析将被用于在 体外细胞系统和动物模型，以鉴定参与逃避的新基因 接触抑制和转移性侵袭。

DESCRIPTION (provided by applicant): Anchorage-independent growth, evasion of contact or cell density-dependent inhibition of growth. Enhanced migration and invasion activities are among the most important properties of in vitro transformed cells. They correlate closely with the characteristics of cancer cells in vivo. The molecular signaling pathways involved in regulating these properties of transformed cells have been investigated by using avian sarcoma virus UR2, which encodes a truncated receptor tyrosine kinase called Ros, and its loss-of-function mutants, as well as a newly discovered Ros down stream effector called Vav3. The results indicate that PI3 kinase and the RhoGTPase signaling pathways play an important role in Ros- and Vav-induced anchorage-independent growth, escape from contact inhibition and enhancment of motility and invasion. The objective of this proposal is to further dissect and identify the down stream signaling pathways of P13 kinase and the RhoGTPases which are important in regulating anchorage-independent growth, evasion of contact inhibition, and motility and invasion of fibroblasts and epithelial cells. In addition, novel genes and pathways important for these transforming properties will be explored. The specific aims are: 1. To elucidate molecular signaling important for anchorage independent growth of cells. 2. To elucidate molecular signaling regulating cell motility and invasion. 3. To explore novel genes and proteins involved in regulating cell motility and invasion. 4. To elucidate the molecular basis for evasion of contact inhibition of growth. Inducible Ros and Vav oncogenes along with various constitutively activated and dominant negative mutants of P13 kinase and Rho GTPases signaling molecules will be used to dissect signaling pathways in transformed fibroblasts and epithelial cells. Microarray and proteomic analysis will be used in the in vitro cell system and animal models to identify novel genes involved in evasion of contact inhibition and metastatic invasion.