Phosphorylation of the Twist1-family basic helix-loop-helix transcription factors is involved in pathological cardiac remodeling.
Phosphorylation of the Twist1-family basic helix-loop-helix transcription factors is involved in pathological cardiac remodeling.
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病理心脏重塑涉及扭曲的基本螺旋 - 环螺旋转录因子的磷酸化。
DOI：
10.1371/journal.pone.0019251
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发表时间：
2011-04-29
期刊：
影响因子：
3.7
通讯作者：
Yang Z
中科院分区：
文献类型：
--
作者：
Lu S;Nie J;Luan Q;Feng Q;Xiao Q;Chang Z;Shan C;Hess D;Hemmings BA;Yang Z
Twist 1家族的碱性螺旋-环-螺旋（bHLH）转录因子包括Twist 1、Hand 1和Hand 2，在心脏发育中起重要作用，并与病理性心脏重塑有关。以前，据报道，这些bHLH转录因子可以调节磷酸化的基本螺旋I结构域，这是参与发育过程，如肢体形成和滋养层分化。然而，Twist 1家族的磷酸化如何在出生后心脏中发挥作用是难以捉摸的。在这里，我们产生了转基因小鼠与过度表达的Hand 1和Twist 1突变体（模仿或取消磷酸化）的心肌细胞，并发现病理性心脏重塑导致心力衰竭和猝死。基因表达谱分析显示，促生长基因上调，代谢基因下调。众所周知，Akt信号传导的异常激活引起病理性心脏重构并导致心力衰竭。Twist 1家族成员的碱性螺旋I结构域含有Akt底物共有基序，可能是Akt信号转导的下游靶点。使用生化分析，我们证明，手1和Twist 1磷酸化Akt的碱性螺旋I结构域。Hand 1的磷酸化调节其荧光素酶报告基因的转录激活和DNA结合能力。该研究为Twist 1家族在心脏重塑中的调节提供了新的见解，并表明Twist 1家族可以受到Akt信号传导的调节。
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. 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. 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.
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DOI：
10.1387/ijdb.082747rb
发表时间：
2009
期刊：
The International journal of developmental biology
影响因子：
--
作者：
Barnes RM;Firulli AB
通讯作者：
Firulli AB
影响因子：
16
作者：
Firulli, BA;Howard, MJ;Firulli, AB
通讯作者：
Firulli, AB
影响因子：
3.9
作者：
Dummler, B.;Hemmings, B. A.
通讯作者：
Hemmings, B. A.
影响因子：
5.3
作者：
Hill, AA;Riley, PR
通讯作者：
Riley, PR
影响因子：
37.8
作者：
DeBosch, B;Treskov, I;Muslin, AJ
通讯作者：
Muslin, AJ