The Ku protein complex interacts with YY1, is up-regulated in human heart failure, and represses alpha myosin heavy-chain gene expression.
Human heart failure is accompanied by repression of genes such as alpha myosin heavy chain (alphaMyHC) and SERCA2A and the induction of fetal genes such as betaMyHC and atrial natriuretic factor. It seems likely that changes in MyHC isoforms contribute to the poor contractility seen in heart failure, because small changes in isoform composition can have a major effect on the contractility of cardiac myocytes and the heart. Our laboratory has recently shown that YY1 protein levels are increased in human heart failure and that YY1 represses the activity of the human alphaMyHC promoter. We have now identified a region of the alphaMyHC promoter that binds a factor whose expression is increased sixfold in failing human hearts. Through peptide mass spectrometry, we identified this binding activity to be a heterodimer of Ku70 and Ku80. Expression of Ku represses the human alphaMyHC promoter in neonatal rat ventricular myocytes. Moreover, overexpression of Ku70/80 decreases alphaMyHC mRNA expression and increases skeletal alpha-actin. Interestingly, YY1 interacts with Ku70 and Ku80 in HeLa cells. Together, YY1, Ku70, and Ku80 repress the alphaMyHC promoter to an extent that is greater than that with YY1 or Ku70/80 alone. Our results suggest that Ku is an important factor in the repression of the human alphaMyHC promoter during heart failure.
Sucharov
Carmen C
CC
Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, USA.
Helmke
Steve M
SM
Langer
Stephen J
SJ
Perryman
M Benjamin
MB
Bristow
Michael
M
Leinwand
Leslie
L
D034961:Antigens, Nuclear / Q000378:metabolism*; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D050981:Erythroid-Specific DNA-Binding Factors; D005786:Gene Expression Regulation / Q000502:physiology; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism*; D000072200:Ku Autoantigen; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000378:metabolism*; D024723:Ventricular Myosins / Q000235:genetics / Q000378:metabolism*; D050986:YY1 Transcription Factor
D034961:Antigens, Nuclear; D004268:DNA-Binding Proteins; D050981:Erythroid-Specific DNA-Binding Factors; D014157:Transcription Factors; D050986:YY1 Transcription Factor; D004247:DNA; D024723:Ventricular Myosins; C000606509:Xrcc6 protein, human; C000606511:Xrcc6 protein, rat; D000072200:Ku Autoantigen