Ras/raf/rho in Lung Cancer Growth and Differentiation

描述：（由申请人提供）这个项目将继续我们的长期 对肺癌细胞调控机制的研究 行为，侧重于ras/raf介导的信号转导途径。我们有 表明RAF激活可诱导小细胞肺癌生长停滞 在小细胞肺癌（SCLC）中，但在非小细胞肺癌（NSCLC）中则不然。 伴随着诱导细胞周期蛋白依赖性激酶抑制剂的表达;在at 至少在某些细胞系中，p27 Kip 1是由翻译控制诱导的。我们 假设！）raf激活可能通过翻译介导生长停滞 控制SCLC细胞，2）这种生长停滞可以通过激活 rho家族蛋白信号转导，可能在NSCLC中更活跃 在SCLC细胞中，和3）raf对SCLC细胞的作用可能部分由以下介导： 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SCLC和NSCLC细胞中检测。在一系列补充研究中， 激活或抑制rho家族信号转导在SCLC细胞中的作用 将进行调查，重点是rho家庭成员对 raf介导的生长停滞。 p27 kip 1在细胞内的翻译激活诱导机制 将研究在SCLC细胞中raf介导的生长停滞。的作用 翻译起始因子eIF 4 E将被检查。的能力 翻译激活以诱导细胞周期蛋白依赖性激酶抑制剂和细胞 将确定SCLC细胞的周期停滞。 自分泌配体在介导raf激活对 将研究SCLC细胞。两种raf诱导的自分泌 将完成肺癌衍生因子LCDF I和LCDF 2。LCDF 1 诱导MAPK磷酸化和p27积累，LCDF 2诱导 SCLC细胞的形态学变化。LCDF I促进生长的能力 逮捕将被确定。LCDF 1的受体将被分离出来， 将鉴定信号转导途径。的表达模式 LCDF 1及其受体和LCDF 2将在肺癌细胞中测定， 线和原发性肿瘤。raf介导的细胞凋亡诱导因子 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.