Transcription Regulation and Biological Function of NAG1

描述(由申请人提供) 非甾体抗炎药(NSAlds)已被用于治疗炎症性疾病。非甾体抗癌药物也具有抗肿瘤活性。一种称为NSAID激活基因-1(NAG-1)的抗肿瘤蛋白，介导了NSAID诱导的抗肿瘤活性的一个分子机制。NAG-1可能参与了NSAlds产生的抗肿瘤和抗炎活性。因此，阐明转录调控和生物学功能为更好地理解癌症和炎症提供了新的机制。研究的目的是研究NSAlds如何调节NAG-1基因的表达，以及环境因素如何影响NAG-1基因调控以预防癌症和炎症。本研究涉及两个具体目标。首先，利用NAG-1基因的启动子来阐明其对NSAID的反应性，然后克隆NSAID反应性结合蛋白。其次，利用纯化的重组NAG-1蛋白和高表达的转基因小鼠对NAG-1的生物学功能进行评价，以阐明其抗肿瘤和抗炎活性。这项提案还试图解决NSAlds如何调控抗肿瘤发生，以及其他被认为调节肿瘤发展的因素是否可以通过改变基因调控来做到这一点。这项研究还可能为化学和环境因素如何影响癌症的发展提供新的见解，并导致新的家族抗肿瘤化合物的开发，这些化合物不是环氧合酶(COX)抑制剂。癌症和炎症当然是与环境相关的问题，因此该项目将提供新的线索，以帮助理解这些药物如何改变肿瘤的发展。

DESCRIPTION (provided by applicant) Nonsteroidal antiinflammatory drugs (NSAlDs) have been used for the treatment of inflammatory disease. NSAlDs also have anti-tumorigenic activity. An anti-tumorigenic protein, called NSAID activated gene-1 (NAG-1), mediates one molecular mechanism for NSAID-induced anti-tumorigenic activity. It is possible that NAG-1 may contribute to anti-tumorigenic and anti-inflammatory activity produced by NSAlDs. Therefore, the elucidation of transcriptional regulation and the biological functions provides a novel mechanism to better understand cancer and inflammation. The research objectives are to study how NSAlDs regulate NAG-1 gene expression, and also how environmental factors may affect-NAG-1 gene regulation to prevent cancer and inflammation. Two specific aims are involved in this research. First, the promoter of NAG-1 gene will be used to elucidate its NSAID responsiveness and then cloning the NSAID responsive binding protein. Secondly, the biological function of NAG-1 will be assessed using purified recombinant NAG-1 protein and NAG-1 overexpressing transgenic mice, to elucidate its anti-tumorigenic and anti-inflammatory activities. This proposal also seeks to address how NSAlDs regulate anti-tumorigenesis, and whether other factors, believed to modulate tumor development, could do so by altering gene regulation. This study may also provide new insights into how chemical and environmental factors influence cancer development and lead to the development of novel family anti-tumorigenic compounds, which are not cyclooxygenase (COX) inhibitors. Cancer and inflammation are certainly environmentally relevant problems and thus this project will provide new clues to aid in the understanding of how these drugs alter tumor development.