Expression of sumoylation deficient Nkx2.5 mutant in Nkx2.5 haploinsufficient mice leads to congenital heart defects

Nkx2.5 is a cardiac specific homeobox gene critical for normal heart development. We previously identified Nkx2.5 as a target of sumoylation, a posttranslational modification implicated in a variety of cellular activities. Sumoylation enhanced Nkx2.5 activity via covalent attachment to the lysine re...

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Bibliographic Details
Published in:PloS one 2011-06, Vol.6 (6), p.e20803-e20803
Main Authors: Kim, Eun Young, Chen, Li, Ma, Yanlin, Yu, Wei, Chang, Jiang, Moskowitz, Ivan P, Wang, Jun
Format: Article
Language:English
Subjects:
Aberration
Animals
Apoptosis
Apoptosis - physiology
Arginine
Biology
Cardiomyocytes
Cardiomyopathy
Cardiomyopathy, Dilated - pathology
Cardiomyopathy, Dilated - physiopathology
Cardiovascular diseases
Cell Proliferation
Congenital diseases
Congenital heart defects
Coronary artery disease
Defects
Deficient mutant
Deoxyribonucleic acid
Developmental biology
DNA
Genes
Genetic disorders
Genetic engineering
Haploinsufficiency
Heart - anatomy & histology
Heart - physiology
Heart attacks
Heart Defects, Congenital - genetics
Heart Defects, Congenital - metabolism
Heart diseases
Heart failure
Homeobox
Homeobox Protein Nkx-2.5
Homeodomain Proteins - genetics
Homeodomain Proteins - metabolism
Humans
Huntingtons disease
Kinases
Laboratories
Lysine
Medicine
Mice
Mice, Knockout
Mice, Transgenic
Morphogenesis
Muscle proteins
Mutants
Mutation
Myocytes, Cardiac - cytology
Myocytes, Cardiac - physiology
Myosin
Nkx2.5 protein
Pathogenesis
Pathology
Phenotypes
Post-translational modifications
Rodents
Science
Small Ubiquitin-Related Modifier Proteins - metabolism
SUMO protein
Sumoylation
Transcription Factors - genetics
Transcription Factors - metabolism
Transgenes
Transgenic mice
Trends
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Description
Summary:Nkx2.5 is a cardiac specific homeobox gene critical for normal heart development. We previously identified Nkx2.5 as a target of sumoylation, a posttranslational modification implicated in a variety of cellular activities. Sumoylation enhanced Nkx2.5 activity via covalent attachment to the lysine residue 51, the primary SUMO acceptor site. However, how sumoylation regulates the activity of Nkx2.5 in vivo remains unknown. We generated transgenic mice overexpressing sumoylation deficient mutant K51R (conversion of lysine 51 to arginine) specifically in mouse hearts under the control of cardiac α-myosin heavy chain (α-MHC) promoter (K51R-Tg). Expression of the Nkx2.5 mutant transgene in the wild type murine hearts did not result in any overt cardiac phenotype. However, in the presence of Nkx2.5 haploinsufficiency, cardiomyocyte-specific expression of the Nkx2.5 K51R mutant led to congenital heart diseases (CHDs), accompanied with decreased cardiomyocyte proliferation. Also, a number of human CHDs-associated Nkx2.5 mutants exhibited aberrant sumoylation. Our work demonstrates that altered sumoylation status may underlie the development of human CHDs associated with Nkx2.5 mutants.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0020803