KRUPPEL LIKE FACTOR DURING INTESTINAL TUMORIGENESIS

富含肠道的kruppel样因子（GKLF）是最近发现的一种转录因子，含有3个C2H2 kruppel型锌指。一些证据表明GKLF是细胞增殖的负调节因子。首先，GKLF的表达与促进生长停滞的条件（如血清剥夺和接触抑制）在时间上相关。第二，GKLF的组成性产生导致DNA合成的抑制。第三，GKLF激活周期蛋白依赖性激酶抑制剂p2l/WAF1/CIP1基因的启动子。第四，GKLF主要在肠有丝分裂后上皮细胞中表达。第五，GKLF在Min小鼠肠道肿瘤形成阶段表达降低。本课题的研究目标是：1)利用Western blot分析、核糖核酸酶保护实验、原位杂交和免疫组织化学检测GKLF在Min小鼠和人正常和肿瘤肠道组织中的表达；2)利用腺病毒介导的基因转移方法研究GKLF负调控细胞生长的机制。

The gut-enriched Kruppel-like factor (GKLF) is a recently identified transcription factor that contains 3 C2H2 Kruppel-type zinc fingers. Several lines of evidence suggest that GKLF is a negative regulator of cellular proliferation. First, expression of GKLF is temporally associated with conditions that promote growth arrest such as serum deprivation and contact inhibition. second, constitutive production of GKLF results in the inhibition of DNA synthesis. Third, GKLF activates the promoter of the cyclin-dependent kinase inhibitor p2l/WAF1/CIP1 gene. Fourth, GKLF is primarily expressed in the post-mitotic epithelial cells of the intestines. Fifth, expression of GKLF is decreased in the intestine of Min mice at the stage when intestinal tumors are formed. The goals of this research proposal are: 1) To examine the expression of GKLF in normal and tumorous intestinal tissues from Min mice and humans using Western blot analysis, ribonuclease protection assay, in situ hybridization and immunohistochemistry and 2) To investigate the mechanisms by which GKLF negatively regulates cell growth using an adenovirus-mediated gene transfer method.