Regulation of the proapoptotic factor FOXO1 (FKHR) in cardiomyocytes by growth factors and alpha1-adrenergic agonists.
Apoptotic responses in cardiomyocytes are opposed by the protein kinase Akt (protein kinase B) and thus can be suppressed by a number of growth factors and cytokines. In some cell types, Akt phosphorylates and inactivates members of the forkhead box (FOXO) family of transcription factors that are active in regulating the expression of proapoptotic cytokines and signaling intermediates. In the current study, we investigated the possibility that FOXO1 (FKHR) was expressed, regulated, and functional in cardiomyocytes. Addition of epidermal growth factor (EGF) (10 nM) to neonatal rat cardiomyocytes caused rapid phosphorylation of Akt and slower FOXO1 phosphorylation. In contrast, the alpha1-adrenergic receptor agonist phenylephrine (50 microM) did not phosphorylate Akt and caused dephosphorylation of FOXO1 acutely and increased FOXO1 expression with chronic exposure. Phenylephrine, but not EGF, caused nuclear translocation of FOXO1, a response that is associated with dephosphorylation. Overexpression of FOXO1 activated transcription of the proapoptotic cytokine, TNFalpha-related apoptosis-inducing ligand, as indicated by reporter gene activity. This response was enhanced by phenylephrine and inhibited by EGF. FOXO1 is expressed, regulated, and functionally active in cardiomyocytes and thus may contribute to apoptotic responses in heart.
Morris
James B
JB
Cellular Biochemistry Laboratory, Baker Heart Research Institute, PO Box 6492, St. Kilda Road Central, Melbourne 8009, Victoria, Australia.
Kenney
Bronwyn
B
Huynh
Huy
H
Woodcock
Elizabeth A
EA
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D018929:Cell Culture Techniques; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000494:pharmacology; D051858:Forkhead Transcription Factors; D005786:Gene Expression Regulation / Q000187:drug effects; D006133:Growth Substances / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects / Q000502:physiology; D006352:Heart Ventricles; D032342:Muscle Cells / Q000166:cytology* / Q000187:drug effects; D009206:Myocardium / Q000166:cytology*; D009419:Nerve Tissue Proteins / Q000187:drug effects / Q000378:metabolism*; D010656:Phenylephrine / Q000494:pharmacology; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D000071161:Forkhead Box Protein O1
D000316:Adrenergic alpha-Agonists; D004268:DNA-Binding Proteins; D004815:Epidermal Growth Factor; D051858:Forkhead Transcription Factors; D006133:Growth Substances; D009419:Nerve Tissue Proteins; D010656:Phenylephrine; C074639:Foxo1 protein, rat; D000071161:Forkhead Box Protein O1