UROKINASE RECEPTOR EXPRESSION--COLON CANCER

描述：此应用程序的目标是确定机制 尿激酶受体(u-PAR)在侵袭性肿瘤中的过度表达 结肠癌。在具体目标1中，申请人提议确定 AP-1上游基序在u-PAR表达调控中的作用 还要鉴定与该序列结合的转录因子。目标2将 确定这些启动子区域在调节u-PAR表达中的作用 通过确定任一区域的缺失是否损害u-PAR启动子活性， 通过鉴定核蛋白接触的核苷酸，以及通过 检测接触核苷酸突变对u-PAR的影响 启动子活性。目标3将确定细胞外的作用 信号调节蛋白1(ERK1)和信号调节蛋白2(ERK2)或组成性激活的MEK1 它位于ERKs的上游，调节u-PAR的表达，并在体外 入侵。目标4将调查一种合成的抑制剂的能力 激活MEK1以下调u-PAR的表达和体外侵袭，以及 AIM 5将确定c-jun氨基末端激酶1(JNK1)在 调节u-PAR的表达。希望这些研究将有益于 降低U-PAR在结肠癌和结肠癌患者中的表达 从而减少疾病的转移性传播。

DESCRIPTION: The goal of this application is to determine the mechanisms leading to the overexpression of the urokinase receptor (u-PAR) in invasive colon cancer. In Specific Aim 1, the applicant proposes to identify the role of an upstream AP-1 motif in the regulation of u-PAR expression and also identify transcription factors bound by this sequence. Aim 2 will ascertain the role of these promoter regions in regulating u-PAR expression by determining if deletion of either region impairs u-PAR promoter activity, by identifying the nucleotides contacted by nuclear proteins, and by determining the effect of mutation of the contacted nucleotides on u-PAR promoter activity. Aim 3 will determine the role of extracellular signal-regulated kinases 1 (ERK1) and 2 or a constitutively activated MEK1 which lies upstream of the ERKs, to modulate u-PAR expression and in vitro invasion. Aim 4 will investigate the ability of a synthetic inhibitor of MEK1 activation to downregulate u-PAR expression and in vitro invasion, and Aim 5 will determine the role of the c-Jun aminoterminal kinase 1 (JNK1) in regulating u-PAR expression. It is hoped that these studies will benefit colon cancer patients by decreasing u-PAR expression in colon cancer and thereby reduce the metastatic spread of the disease.