Regulation of Histidine Decarboxylase

描述（申请人提供）：组氨酸脱羧酶（HDC）是将l -组氨酸转化为组胺的酶，在胃细胞系中起关键作用。目前已经确定了几个调节HDC转录的关键转录因子，包括KLF4、Sp1和YYI。KLF4是在酵母单杂交筛选中发现的，它与上游和下游顺式调控元件结合，抑制AGS细胞的启动子活性。此外，我们还详细介绍了HDC的加工模式，建立了二聚体结构模型，并确定了介导泛素依赖性降解的n端片段。最后，我们在幽门螺杆菌小鼠模型中证明了胃泌素依赖性组胺的产生对胃癌的发展至关重要。这些发现为进一步研究HDC基因的功能和调控奠定了基础，该研究采用了体外和体内两种方法。（1）. 我们将描述转录因子和组蛋白修饰蛋白在HDC启动子调控中的相互作用。（2）. 我们将进一步研究HDC的翻译后调控，并确定E3连接酶。(3)。我们将定义HDC在肿瘤的发展和进展中的作用。总之，这些研究将为HDC基因表达和酶活性的调控及其在胃粘膜中的功能提供新的见解。

DESCRIPTION (provided by applicant): Histidine decarboxylase (HDC) carries out the conversion of L-histidine to histamine and plays a key role in the gastric cell lines. Several of the key transcription factors regulating HDC transcription have been defined, including KLF4, Sp1 and YYI. KLF4, identified in a yeast one-hybrid screen, binds to both upstream and down-stream cis-regulatory elements to inhibit promoter activity in AGS cells. In addition, we have detailed the processing patterns for HDC, developed a model for the dimeric structure, and identified the N-terminal segments mediating ubiquitin-dependent degradation. Finally, we have demonstrated that gastrin-dependent histamine production is critical to the development of gastric cancer in a Helicobacter mouse model. These findings form the foundation for the proposed studies aimed at investigating further the function and regulation of the HDC gene, which utilizes both in vitro and in vivo approaches. (1). We will characterize the interaction between transcription factors and histone modifying proteins in HDC promoter regulation. (2). The post-translational regulation of HDC will be further investigated and the E3 ligases identified. (3). We will define the role for HDC in the development and progression of neoplasia. Overall, these studies will provide new insights into the regulation of HDC gene expression and enzymatic activity, and its function in the gastric mucosa.