Interleukin-1beta is a negative transcriptional regulator of alpha1-adrenergic induced gene expression in cultured cardiac myocytes.
We recently reported that interleukin-1beta (IL-1beta) induces a novel form of cardiac myocyte hypertrophy characterized by an increase in protein content but an absence of the fetal program of skeletal alpha-actin or beta-myosin heavy chain (beta-MHC) gene expression (Palmer, J. N., Hartogensis, W. E., Patten, M., Fortuin, F. D., and Long, C. S. (1995) J. Clin. Invest. 95, 2555-2564). Because of the apparent disparity between this myocardial phenotype and that seen with other hypertrophic agents in culture, such as catecholamines, we investigated the effect of IL-1beta on alpha1-induced cardiomyocyte hypertrophy. Although there was no augmentation in total protein when IL-1beta and phenylephrine were given simultaneously, IL-1beta attenuated the increase in contractile protein mRNAs (skeletal alpha-actin and beta-MHC) in response to phenylephrine. Transient transfection studies with skeletal alpha-actin and beta-MHC promoter constructs linked to the chloramphenicol acetyltransferase (CAT)-reporter gene indicate that repression occurred at the level of gene transcription. In view of the previously reported activity of the zinc finger protein YY1 in the negative regulation of the skeletal alpha-actin promoter in cardiomyocytes (MacLellan, W. R., Lee, T. C., Schwartz, R. J., and Schneider, M. D. (1994) J. Biol. Chem. 269, 16754-16760), we investigated the potential role of this factor in the IL-1beta-mediated effects. Using transient transfection, we found that a mutation in the YY1 binding site of the skeletal alpha-actin promoter abolished the inhibitory effect of IL-1beta. We further found that the 127-base pair fragment of the skeletal alpha-actin promoter required for the IL-1beta effect is also required for inhibition by the overexpression of YY1 in the myocytes. Furthermore, increased levels of YY1 protein are found in IL-1beta treated myocytes. Taken together these results suggest that the repression of contractile protein gene transcription by IL-1beta may be due, at least in part, to activation of the negative transcription factor YY1.
Patten
M
M
Division of Cardiology Section and the Research Service, Veterans Affairs Medical Center, San Francisco, California 94121, USA.
Hartogensis
W E
WE
Long
C S
CS
D000199:Actins / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D002645:Chickens; D015500:Chloramphenicol O-Acetyltransferase / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D050981:Erythroid-Specific DNA-Binding Factors; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000502:physiology; D007375:Interleukin-1 / Q000494:pharmacology*; D008285:Major Histocompatibility Complex / Q000235:genetics; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D010641:Phenotype; D011401:Promoter Regions, Genetic; D051381:Rats; D018340:Receptors, Adrenergic, alpha-1 / Q000502:physiology*; D013045:Species Specificity; D014157:Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects* / Q000502:physiology; D050986:YY1 Transcription Factor
D000199:Actins; D004268:DNA-Binding Proteins; D050981:Erythroid-Specific DNA-Binding Factors; D007375:Interleukin-1; D018340:Receptors, Adrenergic, alpha-1; D014157:Transcription Factors; D050986:YY1 Transcription Factor; C494700:Yy1 protein, rat; D015500:Chloramphenicol O-Acetyltransferase