Regulation of Histidine Decarboxylase

描述(申请人提供)：组氨酸脱羧酶(HDC)负责将L-组氨酸转化为组胺，在胃细胞系中起关键作用。调控HDC转录的几个关键转录因子已被定义，包括KLF4、Sp1和YYI。KLF4在酵母单杂交筛选中被鉴定，它与上游和下游顺式调节元件结合，抑制AGS细胞中的启动子活性。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降解的N-末端片段。最后，我们在幽门螺杆菌小鼠模型中证明了胃泌素依赖组胺的产生对胃癌的发展至关重要。这些发现为旨在进一步研究HDC基因的功能和调控的拟议研究奠定了基础，该研究采用了体外和体内的方法。(1)。我们将研究HDC启动子调控中转录因子和组蛋白修饰蛋白之间的相互作用。(2)。HDC的翻译后调控将进一步研究，并鉴定E3连接酶。(3)。我们将确定HDC在肿瘤的发生和发展中的作用。总体而言，这些研究将为HDC基因表达和酶活性的调节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.