Inbal Rachmin1, Eden Amsalem1, Eliahu Golomb2, Ronen Beeri3, Dan Gilon3, Pengfei Fang4, Hovav Nechushtan5, Gillian Kay1, Min Guo4, Peter Li Yiqing6, Roger S-Y Foo7, David E Fisher8, Ehud Razin9, Sagi Tshori10. 1. Department of Biochemistry and Molecular Biology, The Institute for Medical Research Israel-Canada, Hebrew University Medical School, Jerusalem 91120, Israel. 2. Department of Pathology, Shaare Zedek Medical Center, Jerusalem 91031, Israel. 3. Heart Institute, Hadassah-Hebrew University Medical Center, P.O. Box 12000, Jerusalem 91120, Israel. 4. Department of Cancer Biology, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA. 5. Sharett Institute of Oncology, Hadassah Hebrew University Medical center, P.O. Box 12000, Jerusalem 91120, Israel. 6. Cardiovascular Research institute, Center of Translational Medicine, National University of Singapore, 117599, Singapore. 7. Cardiovascular Research institute, Center of Translational Medicine, National University of Singapore, 117599, Singapore. Electronic address: mdcrfsy@nus.edu.sg. 8. Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Building 149, 13th Street Charlestown, Boston, MA 02129, USA. 9. 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. 10. Department of Nuclear Medicine, Hadassah-Hebrew University Medical Center, P.O. Box 12000, Jerusalem 91120, Israel.
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. METHODS AND 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. CONCLUSION: 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.
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. METHODS AND 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 humanheart failure and plays a role as a negative modulator of pathological cardiac hypertrophy. Here we show that Erbinexpression is regulated by MITF. Under basal conditions MITF activates Erbinexpression by direct binding to its promoter. However, under β-adrenergic stimulation Erbinexpression 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 Erbinexpression. Overexpression of FHL2 alone had no effect on Erbinexpression, but in the presence of MITF, Erbinexpression was decreased. FHL2-MITF association was also increased in biopsies of heart failurepatients. CONCLUSION:MITF unexpectedly regulates both the activation and the repression of Erbinexpression. This ligand mediated fine tuning of its gene expression could be an important mechanism in the process of cardiac hypertrophy and heart failure.
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