TRs have common and isoform-specific functions in regulation of the cardiac myosin heavy chain genes.
TRalpha1 and TRbeta mediate the regulatory effects of T3 and have profound effects on the cardiovascular system. We have analyzed the expression of the cardiac myosin heavy chain (MyHC) genes alpha and beta in mouse strains deficient for one or several TR genes to identify specific regulatory functions of TRalpha1 and TRbeta. The results show that TRalpha1 deficiency, which slows the heart rate, causes chronic overexpression of MyHCbeta. However, MyHCbeta was still suppressible by T3 in both TRalpha1- and TRbeta-deficient mice, indicating that either receptor can mediate repression of MyHCbeta. T3-dependent induction of the positively regulated MyHCalpha gene was similar in both TRalpha1- and TRbeta-deficient mice. The data identify a specific role for TRalpha1 in the negative regulation of MyHCbeta, whereas TRalpha1 and TRbeta appear interchangeable for hormone-dependent induction of MyHCalpha. This suggests that TR isoforms exhibit distinct specificities in the genes that they regulate within a given tissue type. Thus, dysregulation of MyHCbeta is likely to contribute to the critical role of TRalpha1 in cardiac function.
Mansén
A
A
Department of Cell and Molecular Biology, Karolinska Institute, S-171 77 Stockholm, Sweden.
Yu
F
F
Forrest
D
D
Larsson
L
L
Vennström
B
B
D000818:Animals; D015152:Blotting, Northern; D024722:Cardiac Myosins / Q000032:analysis / Q000096:biosynthesis*; D003433:Crosses, Genetic; D004268:DNA-Binding Proteins / Q000502:physiology; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018995:Myosin Heavy Chains / Q000096:biosynthesis* / Q000235:genetics; D020033:Protein Isoforms; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology; D011988:Receptors, Thyroid Hormone / Q000502:physiology*; D014284:Triiodothyronine / Q000097:blood / Q000494:pharmacology
D004268:DNA-Binding Proteins; D020033:Protein Isoforms; D018160:Receptors, Cytoplasmic and Nuclear; D011988:Receptors, Thyroid Hormone; D014284:Triiodothyronine; D024722:Cardiac Myosins; D018995:Myosin Heavy Chains