Ras/raf/rho in Lung Cancer Growth and Differentiation

描述：(申请人提供)该项目将继续我们的长期 对肺癌细胞控制机制的研究兴趣 行为，侧重于ras/raf介导的信号转导通路。我们有 RAF激活可诱导小细胞肺癌生长停滞 (SCLC)，但在非小细胞肺癌(NSCLC)中不是，这种生长停滞是 伴随着细胞周期蛋白依赖性激酶抑制物的表达；在AT 至少部分细胞系p27Kip1是由翻译调控诱导的。我们 假设！)RAF的激活可能通过翻译介导生长停滞 在SCLC细胞中的控制，2)这种生长停滞可以通过激活来阻止 在非小细胞肺癌中可能更活跃的Rho家族蛋白信号转导 3)RAF对SCLC细胞的作用可能部分是通过 自分泌或旁分泌机制。 Rho家族信号转导通路的激活水平将是 在小细胞肺癌和非小细胞肺癌细胞中进行检测。在一系列互补的研究中， 激活或抑制Rho家族信号转导对小细胞肺癌细胞的影响 将被调查，重点是Rho家庭成员对 英国皇家空军介导的生长停滞。 翻译激活诱导p27kip1基因表达的机制 RAF介导的小细胞肺癌细胞生长停滞将被研究。美国政府的角色 翻译启动因子eIF4E将被检验。的能力 翻译激活诱导细胞周期蛋白依赖性激酶抑制物和细胞 小细胞肺癌细胞的周期停滞将被确定。 自分泌配体在介导RAF激活效应中的作用 将对SCLC细胞进行研究。两种RAF诱导的自分泌细胞的鉴定 肺癌衍生因子LCDF I和LCDF2将完成。LCDF 1 诱导MAPK磷酸化和p27积聚，LCDF2诱导 小细胞肺癌细胞的形态变化。LCDF I促进增长的能力 逮捕的决定将会确定。LCDF-1的受体将被分离，其 信号转导途径将被确定。的表达模式 将在肺癌细胞中检测LCDF1及其受体和LCDF2 线条和原发肿瘤。RAF介导的诱生因素的研究进展 将鉴定SCLC细胞中的LCDF-1。

DESCRIPTION: (provided by applicant) This project will continue our long term interest in investigating the mechanisms of control of lung cancer cell behavior, focusing on ras/raf-mediated signal transduction pathways. We have shown that raf activation can induce growth arrest in small cell lung cancer (SCLC), but not in non small cell lung cancer (NSCLC), This growth arrest is accompanied by induction of cyclin dependent kinase inhibitor expression; in at least some cell lines, p27Kip1 is induced by translational control. We hypothesize!) that raf activation may mediate growth arrest via translational control in SCLC cells, 2) that this growth arrest can be blocked by activation of rho family protein signal transduction, which may be more active in NSCLC than in SCLC cells, and 3) raf effects on SCLC cells may be mediated in part by autocrine or paracrine mechanisms. The level of activation of the rho family signal transduction pathway will be examined in SCLC and NSCLC cells. In a complementary series of studies, the effect of activating or inhibiting rho family signal transduction in SCLC cells will be investigated, focusing on the effects of rho family members on raf-mediated growth arrest. The mechanism of induction of p27kip1 by translational activation during raf-mediated growth arrest in SCLC cells will be investigated. The role of the translation initiation factor eIF4E will be examined. The ability of translational activation to induce cyclin dependent kinase inhibitors and cell cycle arrest in SCLC cells will be determined. The role of autocrine ligands in mediating the effects of raf activation in SCLC cells will be investigated. Identification of two raf-induced autocrine lung cancer derived factors, LCDF I and LCDF2, will be completed. LCDF 1 induces Phosphorylation of MAPK and accumulation of p27, and LCDF2 induces morphological changes in SCLC cells. The ability of LCDF I to promote growth arrest will be determined. The receptor for LCDF 1 will be isolated, and its signal transduction pathways will be identified. The expression patterns for LCDF 1 and its receptor, and LCDF2, will be determined in lung cancer cell lines and primary tumors. The factors responsible for raf-mediated induction of LCDF 1 in SCLC cells will be identified.