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.
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