PUBLICATION
AMPK promotes induction of the tumor suppressor FLCN through activation of TFEB independently of mTOR
- Authors
- Collodet, C., Foretz, M., Deak, M., Bultot, L., Metairon, S., Viollet, B., Lefebvre, G., Raymond, F., Parisi, A., Civiletto, G., Gut, P., Descombes, P., Sakamoto, K.
- ID
- ZDB-PUB-190814-6
- Date
- 2019
- Source
- FASEB journal : official publication of the Federation of American Societies for Experimental Biology 33(11): 12374-12391 (Journal)
- Registered Authors
- Civiletto, Gabriele, Gut, Philipp, Parisi, Alice
- Keywords
- 991, AICAR, Birt-Hogg-Dubé syndrome, folliculin, folliculin interacting protein
- MeSH Terms
-
- AMP-Activated Protein Kinases/physiology*
- Active Transport, Cell Nucleus
- Aminoimidazole Carboxamide/analogs & derivatives
- Aminoimidazole Carboxamide/pharmacology
- Animals
- Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/physiology*
- Cells, Cultured
- Gene Expression Profiling
- Hepatocytes/metabolism
- Mice
- Phosphorylation
- Proto-Oncogene Proteins/physiology*
- Ribonucleotides/pharmacology
- TOR Serine-Threonine Kinases/physiology*
- Tumor Suppressor Proteins/physiology*
- Zebrafish
- PubMed
- 31404503 Full text @ FASEB J.
Citation
Collodet, C., Foretz, M., Deak, M., Bultot, L., Metairon, S., Viollet, B., Lefebvre, G., Raymond, F., Parisi, A., Civiletto, G., Gut, P., Descombes, P., Sakamoto, K. (2019) AMPK promotes induction of the tumor suppressor FLCN through activation of TFEB independently of mTOR. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 33(11):12374-12391.
Abstract
AMPK is a central regulator of energy homeostasis. AMPK not only elicits acute metabolic responses but also promotes metabolic reprogramming and adaptations in the long-term through regulation of specific transcription factors and coactivators. We performed a whole-genome transcriptome profiling in wild-type (WT) and AMPK-deficient mouse embryonic fibroblasts (MEFs) and primary hepatocytes that had been treated with 2 distinct classes of small-molecule AMPK activators. We identified unique compound-dependent gene expression signatures and several AMPK-regulated genes, including folliculin (Flcn), which encodes the tumor suppressor FLCN. Bioinformatics analysis highlighted the lysosomal pathway and the associated transcription factor EB (TFEB) as a key transcriptional mediator responsible for AMPK responses. AMPK-induced Flcn expression was abolished in MEFs lacking TFEB and transcription factor E3, 2 transcription factors with partially redundant function; additionally, the promoter activity of Flcn was profoundly reduced when its putative TFEB-binding site was mutated. The AMPK-TFEB-FLCN axis is conserved across species; swimming exercise in WT zebrafish induced Flcn expression in muscle, which was significantly reduced in AMPK-deficient zebrafish. Mechanistically, we have found that AMPK promotes dephosphorylation and nuclear localization of TFEB independently of mammalian target of rapamycin activity. Collectively, we identified the novel AMPK-TFEB-FLCN axis, which may function as a key cascade for cellular and metabolic adaptations.-Collodet, C., Foretz, M., Deak, M., Bultot, L., Metairon, S., Viollet, B., Lefebvre, G., Raymond, F., Parisi, A., Civiletto, G., Gut, P., Descombes, P., Sakamoto, K. AMPK promotes induction of the tumor suppressor FLCN through activation of TFEB independently of mTOR.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping