M-CAT, CArG, and Sp1 elements are required for alpha 1-adrenergic induction of the skeletal alpha-actin promoter during cardiac myocyte hypertrophy. Transcriptional enhancer factor-1 and protein kinase C as conserved transducers of the fetal program in cardiac growth.
Induction of the fetal isogenes skeletal alpha-actin (skACT) and beta-myosin heavy chain (beta-MHC) is characteristic of cardiac growth in many models, suggesting a conserved signaling pathway. However, divergent regulation has also been observed. beta-Protein kinase C (PKC) and transcriptional enhancer factor-1 (TEF-1) are involved in induction of beta-MHC in alpha 1-adrenergic-stimulated hypertrophy of cultured cardiac myocytes (Kariya, K., Farrance, I.K. G., and Simpson, P.C. (1993) J. Biol. Chem. 268, 26658-26662; Kariya, K., Karns, L. R., and Simpson, P.C. (1994) J. Biol. Chem. 269, 3775-3782). In the present study, we asked whether the skACT promoter used the same mechanism. A mouse skACT promoter fragment (-113/-46) was induced by both alpha 1-adrenergic stimulation and co-transfection of activated beta-PKC, and contained three required DNA sequence elements: M-CAT, CArG, and Sp1. The skACT M-CAT element bound TEF-1 in cardiac myocytes. Thus the skACT and beta-MHC promoters both require a TEF-1 binding site for activation by alpha 1-adrenergic stimulation, but differ in that skACT also requires a CArG box. These results provide a potential molecular basis for divergent regulation of the fetal program, and also imply that PKC and TEF-1 are conserved transducers for this program during cardiac growth.
Karns
L R
LR
Division of Cardiology and Research Service, Veterans Affairs Medical Center, San Francisco, California 94121.
Kariya
K
K
Simpson
P C
PC
D000199:Actins / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D006332:Cardiomegaly / Q000378:metabolism*; D002478:Cells, Cultured; D006321:Heart / Q000196:embryology; D007438:Introns; D051379:Mice; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D018340:Receptors, Adrenergic, alpha-1 / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism*
D000199:Actins; D018340:Receptors, Adrenergic, alpha-1; D014157:Transcription Factors; D011493:Protein Kinase C