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Molecular and Cellular Biology, October 2004, p. 8705-8715, Vol. 24, No. 19
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.19.8705-8715.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

The Ku Protein Complex Interacts with YY1, Is Up-Regulated in Human Heart Failure, and Represses {alpha} Myosin Heavy-Chain Gene Expression

Carmen C. Sucharov,1* Steve M. Helmke,2,{dagger} Stephen J. Langer,1 M. Benjamin Perryman,2,{ddagger} Michael Bristow,2 and Leslie Leinwand1

Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder,1 Division of Cardiology, School of Medicine, University of Colorado Health Sciences Center, Denver, Colorado2

Received 8 April 2004/ Returned for modification 4 May 2004/ Accepted 4 July 2004

Human heart failure is accompanied by repression of genes such as {alpha} myosin heavy chain ({alpha}MyHC) and SERCA2A and the induction of fetal genes such as ßMyHC 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 {alpha}MyHC promoter. We have now identified a region of the {alpha}MyHC 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 {alpha}MyHC promoter in neonatal rat ventricular myocytes. Moreover, overexpression of Ku70/80 decreases {alpha}MyHC mRNA expression and increases skeletal {alpha}-actin. Interestingly, YY1 interacts with Ku70 and Ku80 in HeLa cells. Together, YY1, Ku70, and Ku80 repress the {alpha}MyHC 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 {alpha}MyHC promoter during heart failure.

* Corresponding author. Present address: Division of Cardiology, School of Medicine, University of Colorado Health Sciences Center, Denver, CO 80262. Phone: (303) 315-3252. Fax: (303) 315-3261. E-mail: kika.sucharov{at}uchsc.edu.

{dagger} Present address: Cardiovascular Research Institute, University of South Dakota, and Sioux Valley Hospitals and Health Systems, Sioux Falls, SD 57105.

{ddagger} Present address: Colorado Center for Innovative Proteomics, University of Colorado Health Sciences Center, Denver, CO 80262.

Molecular and Cellular Biology, October 2004, p. 8705-8715, Vol. 24, No. 19
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.19.8705-8715.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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