L-Histidine decarboxylase decreases its own transcription through downregulation of ERK activity

A poorly defined negative feedback loop decreases transcription of the L-hi stidine decarboxylase (HDC) gene. To help understand this regulation, we ha ve studied the effect of HDC protein expression on HDC gene transcription i n transfected AGS-B cells. Expression of the rat HDC protein inhibited HDC promoter activity in a dose-dependent fashion. The region of the HDC promot er mediating this inhibitory effect corresponded to a previously defined ga strin and extracellular signal-related kinase (ERK)-1 response element. Ove rexpression of the HDC protein reduced nuclear factor binding in this regio n. Experiments employing specific histamine receptor agonists indicated tha t the inhibitory effect was not dependent on histamine production, and stud ies with the HDC inhibitor alpha -fluoromethylhistidine revealed that inhib ition was unrelated to enzyme activity. Instead, an enzymatically inactive region at the amino terminal of the HDC enzyme (residues 1-271) was shown t o mediate inhibition. Fluorescent chimeras containing this domain were not targeted to the nucleus, arguing against specific inhibition of the HDC tra nscription machinery. Instead, we found that overexpression of HDC protein decreased ERK protein levels and ERK activity and that the inhibitory effec t of HDC protein could be overcome by overexpression of ERK1. These data su ggest a novel feedback-inhibitory role for amino terminal sequences of the HDC protein.