title: FHL2 switches MITF from activator to repressor of Erbin expression during cardiac hypertrophy.
abstract: BACKGROUND
  Congestive heart failure (CHF) is a significant health care burden in developed countries. However, the molecular events leading from cardiac hypertrophy to CHF are unclear and preventive therapeutic approaches are limited. We have previously described that microphthalmia-associated transcription factor (MITF) is a key regulator of cardiac hypertrophy, but its cardiac targets are still uncharacterized.
  
  
  RESULTS
  Gene array analysis of hearts from MITF-mutated mice indicated that ErbB2 interacting protein (Erbin) is a candidate target gene for MITF. We have recently demonstrated that Erbin is decreased in human heart failure and plays a role as a negative modulator of pathological cardiac hypertrophy. Here we show that Erbin expression is regulated by MITF. Under basal conditions MITF activates Erbin expression by direct binding to its promoter. However, under β-adrenergic stimulation Erbin expression is decreased only in wild type mice, but not in MITF-mutated mice. Yeast two-hybrid screening, using MITF as bait, identified an interaction with the cardiac-predominant four-and-a-half LIM domain protein 2 (FHL2), which was confirmed by co-immunoprecipitation in both mouse and human hearts. Upon β-adrenergic stimulation, FHL2 and MITF bind Erbin promoter as a complex and repress MITF-directed Erbin expression. Overexpression of FHL2 alone had no effect on Erbin expression, but in the presence of MITF, Erbin expression was decreased. FHL2-MITF association was also increased in biopsies of heart failure patients.
  
  
  CONCLUSIONS
  MITF unexpectedly regulates both the activation and the repression of Erbin expression. This ligand mediated fine tuning of its gene expression could be an important mechanism in the process of cardiac hypertrophy and heart failure.
authors.affiliation: Department of Biochemistry and Molecular Biology, The Institute for Medical Research Israel-Canada, Hebrew University Medical School, Jerusalem 91120, Israel.
authors.forename: Inbal
authors.initials: I
authors.lastname: Rachmin
authors.affiliation: Department of Biochemistry and Molecular Biology, The Institute for Medical Research Israel-Canada, Hebrew University Medical School, Jerusalem 91120, Israel.
authors.forename: Eden
authors.initials: E
authors.lastname: Amsalem
authors.affiliation: Department of Pathology, Shaare Zedek Medical Center, Jerusalem 91031, Israel.
authors.forename: Eliahu
authors.initials: E
authors.lastname: Golomb
authors.affiliation: Heart Institute, Hadassah-Hebrew University Medical Center, P.O. Box 12000, Jerusalem 91120, Israel.
authors.forename: Ronen
authors.initials: R
authors.lastname: Beeri
authors.affiliation: Heart Institute, Hadassah-Hebrew University Medical Center, P.O. Box 12000, Jerusalem 91120, Israel.
authors.forename: Dan
authors.initials: D
authors.lastname: Gilon
authors.affiliation: Department of Cancer Biology, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA.
authors.forename: Pengfei
authors.initials: P
authors.lastname: Fang
authors.affiliation: Sharett Institute of Oncology, Hadassah Hebrew University Medical center, P.O. Box 12000, Jerusalem 91120, Israel.
authors.forename: Hovav
authors.initials: H
authors.lastname: Nechushtan
authors.affiliation: Department of Biochemistry and Molecular Biology, The Institute for Medical Research Israel-Canada, Hebrew University Medical School, Jerusalem 91120, Israel.
authors.forename: Gillian
authors.initials: G
authors.lastname: Kay
authors.affiliation: Department of Cancer Biology, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Guo
authors.affiliation: Cardiovascular Research institute, Center of Translational Medicine, National University of Singapore, 117599, Singapore.
authors.forename: Peter Li
authors.initials: PL
authors.lastname: Yiqing
authors.affiliation: Cardiovascular Research institute, Center of Translational Medicine, National University of Singapore, 117599, Singapore. Electronic address: mdcrfsy@nus.edu.sg.
authors.forename: Roger S-Y
authors.initials: RS
authors.lastname: Foo
authors.affiliation: Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Building 149, 13th Street Charlestown, Boston, MA 02129, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Fisher
authors.affiliation: Department of Biochemistry and Molecular Biology, The Institute for Medical Research Israel-Canada, Hebrew University Medical School, Jerusalem 91120, Israel. Electronic address: ehudr@ekmd.huji.ac.il.
authors.forename: Ehud
authors.initials: E
authors.lastname: Razin
authors.affiliation: Department of Nuclear Medicine, Hadassah-Hebrew University Medical Center, P.O. Box 12000, Jerusalem 91120, Israel.
authors.forename: Sagi
authors.initials: S
authors.lastname: Tshori
mesh_terms: D000818:Animals; D001706:Biopsy; D006332:Cardiomegaly / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000502:physiology*; D006333:Heart Failure / Q000473:pathology; D006352:Heart Ventricles / Q000473:pathology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D060850:LIM-Homeodomain Proteins / Q000378:metabolism*; D008297:Male; D051379:Mice; D051739:Microphthalmia-Associated Transcription Factor / Q000378:metabolism*; D009124:Muscle Proteins / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation / Q000502:physiology
chemical_list: D002352:Carrier Proteins; C498804:Erbb2ip protein, mouse; C491382:Fhl2 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D060850:LIM-Homeodomain Proteins; D051739:Microphthalmia-Associated Transcription Factor; C497235:Mitf protein, mouse; D009124:Muscle Proteins; D014157:Transcription Factors
keywords: Activator; Erbin; FHL2; Gene regulation; MITF; Repressor