UROKINASE RECEPTOR EXPRESSION--COLON CANCER

描述：本应用程序的目标是确定 导致尿激酶受体（u-PAR）过度表达， 结肠癌 在具体目标1中，申请人建议确定 上游AP-1基序在调节u-PAR表达中的作用， 还鉴定了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， 测定所接触的核苷酸的突变对u-PAR的影响， 启动子活性 目的3将确定细胞外的作用 信号调节激酶1（ERK 1）和2或组成型激活的MEK 1 其位于ERK的上游，以调节u-PAR表达，并且在体外 入侵 目的4将研究一种合成的抑制剂的能力， MEK 1活化下调u-PAR表达和体外侵袭，以及 目的5将确定c-Jun氨基末端激酶1（JNK 1）在 调节u-PAR表达。 希望这些研究将有助于 通过降低结肠癌中u-PAR的表达， 从而减少疾病的转移性扩散。

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.