This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sucharov, C. C. Articles by Leinwand, L. Search for Related Content PubMed PubMed Citation Articles by Sucharov, C. C. Articles by Leinwand, L.

 Previous Article  |  Next Article 

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 Myosin Heavy-Chain Gene Expression

Carmen C. Sucharov,^1* Steve M. Helmke,^2, Stephen J. Langer,¹ M. Benjamin Perryman,^2, 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 myosin heavy chain (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 MyHC promoter. We have now identified a region of the 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 MyHC promoter in neonatal rat ventricular myocytes. Moreover, overexpression of Ku70/80 decreases MyHC mRNA expression and increases skeletal -actin. Interestingly, YY1 interacts with Ku70 and Ku80 in HeLa cells. Together, YY1, Ku70, and Ku80 repress the 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 MyHC promoter during heart failure.

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

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

This article has been cited by other articles:

• Pillai, J. B., Chen, M., Rajamohan, S. B., Samant, S., Pillai, V. B., Gupta, M., Gupta, M. P. (2008). Activation of SIRT1, a class III histone deacetylase, contributes to fructose feeding-mediated induction of the {alpha}-myosin heavy chain expression. Am. J. Physiol. Heart Circ. Physiol. 294: H1388-H1397 [Abstract] [Full Text]  
• Wang, H., Hertlein, E., Bakkar, N., Sun, H., Acharyya, S., Wang, J., Carathers, M., Davuluri, R., Guttridge, D. C. (2007). NF-{kappa}B Regulation of YY1 Inhibits Skeletal Myogenesis through Transcriptional Silencing of Myofibrillar Genes. Mol. Cell. Biol. 27: 4374-4387 [Abstract] [Full Text]  
• Idogawa, M., Masutani, M., Shitashige, M., Honda, K., Tokino, T., Shinomura, Y., Imai, K., Hirohashi, S., Yamada, T. (2007). Ku70 and Poly(ADP-Ribose) Polymerase-1 Competitively Regulate {beta}-Catenin and T-Cell Factor-4-Mediated Gene Transactivation: Possible Linkage of DNA Damage Recognition and Wnt Signaling. Cancer Res. 67: 911-918 [Abstract] [Full Text]  
• Lee, S.-G., Su, Z.-Z., Emdad, L., Sarkar, D., Fisher, P. B. (2006). Astrocyte elevated gene-1 (AEG-1) is a target gene of oncogenic Ha-ras requiring phosphatidylinositol 3-kinase and c-Myc. Proc. Natl. Acad. Sci. USA 103: 17390-17395 [Abstract] [Full Text]  
• Sucharov, C. C., Langer, S., Bristow, M., Leinwand, L. (2006). Shuttling of HDAC5 in H9C2 cells regulates YY1 function through CaMKIV/PKD and PP2A. Am. J. Physiol. Cell Physiol. 291: C1029-C1037 [Abstract] [Full Text]