Regulation of adrenomedullin gene transcription and degradation by the c-myc gene.
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.
Ozawa
Naoko
N
Tokyo Medical and Dental University Medical Hospital, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
Shichiri
Masayoshi
M
Fukai
Nozomi
N
Yoshimoto
Takanobu
T
Hirata
Yukio
Y
D053607:Adrenomedullin; D000818:Animals; D002460:Cell Line; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D008156:Luciferases / Q000235:genetics; D010455:Peptides / Q000235:genetics* / Q000378:metabolism*; D010957:Plasmids; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D014158:Transcription, Genetic / Q000502:physiology
D010455:Peptides; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D053607:Adrenomedullin; D008156:Luciferases