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FOXO Transcription Factors are Critical regulators of Neonatal Cardiomyocyte Proliferation
Author(s) -
Sengupta Arunima,
Yutzey katherine E
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.525.6
Subject(s) - foxo1 , foxm1 , foxo3 , chromatin immunoprecipitation , cell growth , transcription factor , microbiology and biotechnology , activator (genetics) , cell cycle , biology , cancer research , signal transduction , gene expression , cell , protein kinase b , promoter , gene , genetics
Cardiomyocytes (CM) are highly proliferative during embryogenesis and withdraw from the cell cycle soon after birth. Here, the role of FOXO in regulating CM proliferation in neonatal cardiomyocytes in mice is investigated. CM‐specific deficiency of FOXO1 and FOXO3 results in increased CM proliferation 1–3 days after birth. Inhibition of AMP‐activated protein kinase (AMPK), an upstream activator of FOXO, increases proliferation in cultured rat neonatal CM and this increase is attenuated with overexpression of FOXO1 supporting the requirement of an active AMPK/FOXO signaling to promote cell cycle withdrawal in neonatal CM. FOXM1 and IGF1 both promote CM proliferation, and CM‐specific loss of FOXOs results in increased expression of FOXM1 and IGF1. Furthermore, FOXO1 and FOXO3 directly bind to regulatory regions of FOXM1 in neonatal cardiomyocytes, and FOXO1 inhibits FOXM1 reporter gene expression in cotransfection assays. We identified IGF1 as a direct transcriptional target of FOXM1 by chromatin immunoprecipitation assay. These results suggest that FOXO activity inhibits FOXM1 thereby controlling IGF1 levels to promote cell cycle withdrawal in neonatal CM. Therefore, understanding the molecular mechanisms by which FOXO regulates CM proliferation could be harnessed in adults for the treatment of cardiac injury. This work is supported by an AHA Post‐Doctoral Fellowship to AS and NIH P01HL069779 to KEY. Grant Funding Source : NIH P01HL069779 to KEY and AHA postdoctoral fellowship to AS