title: Phosphorylation of the Twist1-family basic helix-loop-helix transcription factors is involved in pathological cardiac remodeling.
abstract: 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.
  
  
  RESULTS
  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.
authors.affiliation: The Ministry of Education Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, China.
authors.forename: Shuangshuang
authors.initials: S
authors.lastname: Lu
authors.forename: Junwei
authors.initials: J
authors.lastname: Nie
authors.forename: Qing
authors.initials: Q
authors.lastname: Luan
authors.forename: Qiuting
authors.initials: Q
authors.lastname: Feng
authors.forename: Qi
authors.initials: Q
authors.lastname: Xiao
authors.forename: Zai
authors.initials: Z
authors.lastname: Chang
authors.forename: Congjia
authors.initials: C
authors.lastname: Shan
authors.forename: Daniel
authors.initials: D
authors.lastname: Hess
authors.forename: Brian A
authors.initials: BA
authors.lastname: Hemmings
authors.forename: Zhongzhou
authors.initials: Z
authors.lastname: Yang
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D004452:Echocardiography / Q000379:methods; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009206:Myocardium / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics* / Q000502:physiology*; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors / Q000378:metabolism; D051879:Twist-Related Protein 1 / Q000235:genetics* / Q000502:physiology*; D020257:Ventricular Remodeling / Q000235:genetics*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D009687:Nuclear Proteins; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D051879:Twist-Related Protein 1; C095572:Hand1 protein, mouse; C103173:TWIST1 protein, human; C067250:Twist1 protein, mouse