Molecular mechanisms of gastrin-dependent gene regulation.
The peptide hormone gastrin is the key regulator of gastric acid secretion. Gastrin exerts its effects as acid secretagogue through functional activation of gastric enterochromaffin-like (ECL) cells, which control acid secretion through biosynthesis and release of histamine. In ECL cells, concerted activation of histidine decarboxylase (HDC), vesicular monoamine transporter 2 (VMAT2), and chromogranin A (CgA) genes by gastrin is a prerequisite for proper acid control. To elucidate the molecular pathways underlying gastrin-dependent control of ECL cell genes, we recently analyzed the signaling cascades, regulatory promoter elements, and transcription factors mediating the transcriptional effects of gastrin. Our studies identified the Raf>MEK1>ERK 1/-2 kinase module as the common signaling pathway mediating gastrin-dependent ECL cell gene transcription. In contrast to this uniform signaling cascade, pronounced heterogeneity was detected between cis- and trans-activating regulatory factors conferring gastrin responsiveness. The molecular diversity of transcription factors and regulatory enhancer elements transmitting gastrin-triggered gene transcription offers the molecular basis for synergistic, but differential, regulation of HDC, VMAT2, and CgA genes during a secretory challenge of ECL cells by gastrin and possibly other acid secretagogues.
Hocker
Michael
M
Medizinische Klink mit Schwerpunkt Gastroenterologie und Hepatologie, Charité -- Universitätsmedizin Berlin, Campus Virchow-Klinikum, 13353 Berlin, Germany. michael.hoecker@charite.de
D000818:Animals; D004759:Enterochromaffin Cells / Q000502:physiology*; D005755:Gastrins / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D015398:Signal Transduction / Q000502:physiology
D005755:Gastrins