Phosphorylation of the Twist1-family basic helix-loop-helix transcription factors is involved in pathological cardiac remodeling
| Autor: | Zai Chang, Daniel Hess, Junwei Nie, Congjia Shan, Qi Xiao, Shuangshuang Lu, Zhongzhou Yang, Qiuting Feng, Brian A. Hemmings, Qing Luan |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
Mouse
Developmental Signaling lcsh:Medicine Cardiovascular Mice Twist transcription factor Molecular Cell Biology Basic Helix-Loop-Helix Transcription Factors Phosphorylation lcsh:Science Multidisciplinary Ventricular Remodeling biology Heart development Nuclear Proteins Animal Models Signaling in Selected Disciplines Signaling Cascades Cell biology Echocardiography Medicine Cardiomyopathies HAND2 Plasmids Research Article Signal Transduction animal structures Recombinant Fusion Proteins Mice Transgenic Sudden death Model Organisms Akt Signaling Cascade medicine Animals Humans Ventricular remodeling Biology Protein kinase B Transcription factor Heart Failure Myocardium Twist-Related Protein 1 lcsh:R medicine.disease Molecular biology Mutation biology.protein lcsh:Q Transcription Factors |
| Zdroj: | PLoS ONE, Vol 6, Iss 4, p e19251 (2011) PLoS ONE |
| ISSN: | 1932-6203 |
| Popis: | Background The Twist1-family basic helix-loop-helix (bHLH) transcription factors including Twist1, Hand1 and Hand2, play an essential role in heart development and are implicated in pathological heart remodeling. Previously, it was reported that these bHLH transcription factors can be regulated by phosphorylation within the basic-helix I domain, which is involved in developmental processes such as limb formation and trophoblast differentiation. However, how phosphorylation of Twist1 family functions in post-natal heart is elusive. Principal Findings Here, we generated transgenic mice with over-expression of Hand1 and Twist1 mutants (to mimic or to abolish phosphorylation) in cardiomyocytes and found pathological cardiac remodeling leading to heart failure and sudden death. Gene expression profile analysis revealed up-regulation of growth-promoting genes and down-regulation of metabolic genes. It is well known that aberrant activation of Akt signaling causes pathological cardiac remodeling and results in heart failure. The basic-helix I domain of Twist1 family members contain Akt substrate consensus motif and may be downstream targets of Akt signaling. Using biochemical analysis, we demonstrated that Hand1 and Twist1 were phosphorylated by Akt in the basic-helix I domain. Phosphorylation of Hand1 regulated its transcriptional activation of luciferase reporter genes and DNA binding ability. Conclusions This study provides novel insights into the regulation of Twist1 family in cardiac remodeling and suggests that the Twist1 family can be regulated by Akt signaling. |
| Databáze: | OpenAIRE |
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