Positive regulation of the skeletal alpha-actin gene by Fos and Jun in cardiac myocytes.
Transcription of the skeletal alpha-actin gene is selectively activated in rat myocardiocytes undergoing hypertrophy both in vivo and in vitro. In most of these models, transient expression of certain proto-oncogene transcription factors precedes hypertrophy and sarcomeric gene induction. Using expression vectors encoding Fos and Jun, the main constituents of transcriptional activator protein AP-1, we analyzed the role of these oncoproteins in mediating the transcriptional induction of skeletal alpha-actin by adrenergic stimulation. Both c-fos and c-jun were induced early after beta-adrenergic stimulation, with peak mRNA levels preceding skeletal alpha-actin induction by several hours. A second peak of c-jun mRNA coincided with skeletal alpha-actin induction. Co-transfection assays in cardiac myocytes and P19 teratocarcinoma cells demonstrated that over-expression of c-jun, or c-fos plus c-jun, transactivated the skeletal alpha-actin promoter by about 5-fold. Comparable activation was not seen for alpha-myosin heavy chain or cardiac alpha-actin promoters. Skeletal alpha-actin promoter sequences between -153 and -36 were required for maximal transactivation by c-fos/c-jun, and purified Fos and Jun were bound specifically within this region. A direct physiological role is suggested for the AP-1 transcription factor complex in regulating skeletal alpha-actin gene expression and alpha-actin isoform switching during the onset of signal-mediated cardiac myocyte hypertrophy.
Bishopric
N H
NH
Life Sciences Division, SRI International, Menlo Park, California 94025.
Jayasena
V
V
Webster
K A
KA
D000199:Actins / Q000235:genetics*; D000818:Animals; D000831:Animals, Newborn; D001483:Base Sequence; D002478:Cells, Cultured; D015500:Chloramphenicol O-Acetyltransferase / Q000235:genetics / Q000378:metabolism; D016762:Genes, fos; D016758:Genes, jun; D006801:Humans; D008969:Molecular Sequence Data; D009132:Muscles / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D009838:Oligodeoxyribonucleotides; D010957:Plasmids; D011401:Promoter Regions, Genetic; D000090063:Proto-Oncogene Mas; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D015533:Transcriptional Activation; D014162:Transfection
D000199:Actins; C000715470:MAS1 protein, human; D009838:Oligodeoxyribonucleotides; D000090063:Proto-Oncogene Mas; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D011994:Recombinant Proteins; D015500:Chloramphenicol O-Acetyltransferase