Regulation of Adrenomedullin Gene Transcription and Degradation by the c-mycGene

Adrenomedullin, a vasodilatory peptide originally isolated from pheochromocytoma, is known to regulate cell growth, apoptosis, and migration. Overexpression of the c-myc oncogene has been shown to suppress the mouse adrenomedullin gene via the initiator element. We investigated whether c-myc regulates rat and human adrenomedullin genes because there appears to be no initiator elements in their promoter regions. Transactivation of the human adrenomedullin gene by c-myc was demonstrated using a luciferase reporter construct containing an upstream sequence. Using a panel of isogenic rat fibroblast cell lines with differential c-myc expression obtained by targeted homologous recombination, we found markedly elevated adrenomedullin transcript levels in cells stably overexpressing c-myc but a minimal decrease in two independent cell lines containing a homozygous null deletion of c-myc. Degradation of adrenomedullin mRNA was enhanced by a c-myc transgene, resulting in a relatively reserved increase in cellular secretion of adrenomedullin-like immunoreactivity. These results indicate that c-myc transactivates rat and human adrenomedullin genes and accelerates the degradation rate of adrenomedullin mRNA. However, c-myc is not essential for basal expression of the adrenomedullin gene.