Regulation of Histidine Decarboxylase

组氨酸脱羧酶的调节

• 批准号: 7447375
• 负责人: Timothy Cragin Wang
• 金额: $ 35.16万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-01-30 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7447375
• 关键词: Acids; Binding; Cell Line; Cells; Data; Degradation Pathway; Development; Enterochromaffin-like Cells; Enzymes; Epithelial Cells; Event; Foundations; Funding; Gastric mucosa; Gastrins; Gene Expression; Genes; Genetic Transcription; Growth; Helicobacter; Helicobacter felis; Histamine; Histamine H2 Receptors; Histamine Production; Histidine; Histidine Decarboxylase; Histones; Hybrids; In Vitro; Inflammatory; Infusion procedures; Knockout Mice; Laboratories; LacZ Genes; Mediating; Modeling; Molecular; Mus; N-terminal; Neoplasms; Nuclear; Pathway interactions; Pattern; Phosphorylation; Play; Post-Translational Regulation; Process; Protein Isoforms; Proteins; Receptor Signaling; Regulation; Regulatory Element; Role; Stomach; Stream; Structure; Transgenic Mice; Ubiquitin; Ubiquitination; Work; Yeasts; base; cell growth; dimer; feeding; in vivo; insight; malignant stomach neoplasm; mouse model; multicatalytic endopeptidase complex; promoter; response; three dimensional structure; transcription factor; ubiquitin-protein ligase

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.

描述（由申请方提供）：组氨酸脱羧酶（HDC）将L-组氨酸转化为组胺，在胃细胞系中起关键作用。已经确定了几种调节HDC转录的关键转录因子，包括KLF 4、Sp1和YYI。在酵母单杂交筛选中鉴定的KLF 4结合上游和下游顺式调节元件以抑制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，开发了二聚体结构模型，并确定了介导泛素依赖性降解的N-末端片段。最后，我们已经证明，胃泌素依赖性组胺的生产是至关重要的胃癌的发展，在螺杆菌小鼠模型。这些发现为进一步研究HDC基因的功能和调控奠定了基础，该研究利用体外和体内方法。（一）.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。（二）、将进一步研究HDC的翻译后调节，并鉴定E3连接酶。（三）、我们将明确HDC在肿瘤发生和发展中的作用。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。