miR-139 impacts FoxO1 action by decreasing FoxO1 protein in mouse hepatocytes.
FoxO1 is a master regulator of signaling pathways used by growth factors and hormones, including insulin. Its activity is regulated by changes in subcellular localization coupled to post-translational modifications such as phosphorylation, ubiquitination, and acetylation. As microRNAs have emerged as a newly identified means by which cells fine-tune gene expression, we hypothesized that they could regulate FoxO1. Since FoxO1 plays a key role in the liver, we used immortalized neonatal mouse hepatocytes to analyze the effects of potential microRNAs targeting FoxO1. We found that miR-139 targets FoxO1 mRNA directly and reduces the level of the protein without affecting transcript levels. This decrease in FoxO1 protein results in a decrease of its target genes, such as AdQR1, AdQR2 and Mttp. Our findings suggest a novel mode of FoxO1 regulation by which miR-139 could maintain the protein level of FoxO1 to preserve homeostatic regulation of its transcriptional activity in response to environmental stimuli.
Hasseine
Larbi Kamal
LK
INSERM U907, Nice F-06107, France.
Hinault
Charlotte
C
Lebrun
Patricia
P
Gautier
Nadine
N
Paul-Bellon
Rachel
R
Van Obberghen
Emmanuel
E
D000818:Animals; D002478:Cells, Cultured; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000378:metabolism*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; C546202:MIRN139 microRNA, mouse; D035683:MicroRNAs; D012333:RNA, Messenger