title: FOXO3 is a glucocorticoid receptor target and regulates LKB1 and its own expression based on cellular AMP levels via a positive autoregulatory loop.
abstract: FOXO3 is a transcription factor involved in the regulation of multiple physiological processes including cell cycle arrest, apoptosis, oxidative stress-response and energy metabolism. Although much is known about its post-translational modification, the transcriptional regulation of FOXO3, as well as the cross-talk between transcription and post-translational events, is still poorly understood. In the present study, we show that FOXO3 is an immediate early glucocorticoid receptor (GR) target, whose transcription is even further enhanced by conditions that mimic metabolic stress. Induction of FOXO3 transcription by GR-binding steroids was reversed by concomitant treatment with the GR antagonist RU-486, but further enhanced by stimuli that activate the AMP-activated protein kinase (AMPK). Analysis of genomic DNA and chromatin immunoprecipitation, as well as luciferase reporter assays, revealed two functional glucocorticoid responsive elements within the FOXO3 promoter. Furthermore, we provide functional evidence for a phosphorylation switch that explains how glucocorticoids induce transcriptional activation of the gene but subsequently inactivate the corresponding protein by site-specific phosphorylation. Only when AMPK is stimulated, pre-existing FOXO3 becomes reverted toward an active form. Energy deprived conditions thus activate FOXO3 on two different levels, namely transcriptional and post-translational. In that way, FOXO3 acts as a metabolic stress sensor that coordinates expression of LKB1, the master upstream kinase involved in metabolic sensing, depending on the energy status of the cell. Additionally, we show that FOXO3 binds and activates its own promoter via a positive autoregulatory feedback loop. In conclusion, our data explain how catabolic glucocorticoid hormones and high intracellular AMP levels cooperate in inducing FOXO3 transcription and in activating the corresponding protein.
authors: Research Program Infections and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany. nicolas.luetzner@web.de
authors: Nicolas
authors: N
authors: Lützner
authors: Hubert
authors: H
authors: Kalbacher
authors: Anja
authors: A
authors: Krones-Herzig
authors: Frank
authors: F
authors: Rösl
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000249:Adenosine Monophosphate / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D000249:Adenosine Monophosphate; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D005938:Glucocorticoids; D017874:Immediate-Early Proteins; D007328:Insulin; D017346:Protein Serine-Threonine Kinases; D011965:Receptors, Glucocorticoid; D000099184:Serum-Glucocorticoid Regulated Kinases; C499517:FOXO3 protein, human; C109790:STK11 protein, human