TGF-beta 1 and fibroblast growth factors selectively up-regulate tissue-specific fetal genes in cardiac muscle cells.
TGF-beta 1, like basic and acidic fibroblast growth factor (FGF), inhibits differentiated gene expression in skeletal myoblasts. It potentiates FGF-beta 1 down-regulated expression of the alpha-myosin heavy chain gene and the sarcoplasmic reticulum calcium ATPase gene, yet up-regulated expression of the genes for beta-myosin heavy chain, atrial natriuretic factor, and both skeletal and smooth muscle alpha-actin-four transcripts associated with the embryonic heart. TGF-beta 1 did not affect cardiac alpha-actin gene expression. These responses resemble the generalized 'fetal' phenotype seen during hypertrophy triggered by a haemodynamic load. Chick skeletal and cardiac alpha-actin promoter-driven reported genes were transfected into neonatal rat cardiac myocytes. TGF-beta 1 stimulated skeletal alpha-actin transcription, but not transcription from the cardiac alpha-actin promoter. Basic FGF produced the same results as TGF-beta 1, but acidic FGF suppressed expression of both alpha-actin genes; these results were true for purified and recombinant FGFs. Modulation of alpha-actin transcription by growth factors corresponded accurately to control of the endogenous genes. Three positive cis-acting elements were critical for skeletal alpha-actin transcription in cardiac, as well as skeletal, myocytes, particularly the downstream CCAAT box-associated repeat. Thus, TGF-beta 1 and FGFs selectively induce an ensemble of 'fetal' genes and differentially regulate alpha-actin transcription in cardiac muscle cells.
Parker
T G
TG
Department of Medicine, Baylor College of Medicine, Houston, TX 77030-3498.
Chow
K L
KL
Schwartz
R J
RJ
Schneider
M D
MD
D000199:Actins / Q000096:biosynthesis / Q000235:genetics; D002455:Cell Division / Q000187:drug effects; D005318:Fetal Heart / Q000378:metabolism; D016220:Fibroblast Growth Factor 1 / Q000494:pharmacology*; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D009124:Muscle Proteins / Q000096:biosynthesis* / Q000235:genetics; D009206:Myocardium / Q000166:cytology*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D000199:Actins; D009124:Muscle Proteins; D016212:Transforming Growth Factor beta; D016222:Fibroblast Growth Factor 2; D016220:Fibroblast Growth Factor 1