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PMID: 15367688 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

The Ku protein complex interacts with YY1, is up-regulated in human heart failure, and represses alpha myosin heavy-chain gene expression.

Molecular and cellular biology ·Vol. 24 ·No. 19 ·2004-10-00 ·Pages 8705-15

Sucharov CC, Helmke SM, Langer SJ, Perryman MB, Bristow M, Leinwand L

Abstract

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.

MeSH Terms
Antigens, Nuclear/metabolism DNA/metabolism DNA-Binding Proteins/metabolism Erythroid-Specific DNA-Binding Factors Gene Expression Regulation/physiology Heart Failure/genetics,metabolism Ku Autoantigen Promoter Regions, Genetic Transcription Factors/metabolism Ventricular Myosins/genetics,metabolism YY1 Transcription Factor
Chemicals
Antigens, Nuclear DNA-Binding Proteins Erythroid-Specific DNA-Binding Factors Transcription Factors YY1 Transcription Factor DNA Ventricular Myosins Xrcc6 protein, human Xrcc6 protein, rat Ku Autoantigen
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Sucharov Carmen C
Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, USA.
Helmke Steve M
Langer Stephen J
Perryman M Benjamin
Bristow Michael
Leinwand Leslie
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.24.19.8705-8715.2004
Published
2004-10-00
Pages
8705-15
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC516749
Subset
IM
Grants
NHLBI NIH HHS · R01 HL56510 · United States
External Links
PubMed source DOI: 10.1128/MCB.24.19.8705-8715.2004 PMC Full Text View journal details
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