DOI: 10.1101/499921Dec 20, 2018Paper

AMPK promotes induction of a tumor suppressor FLCN through activation of TFEB independently of mTOR

BioRxiv : the Preprint Server for Biology
Caterina CollodetKei Sakamoto

Abstract

AMP-activated protein kinase (AMPK) is a central energy sensor and master regulator of energy homeostasis. AMPK not only elicits acute metabolic responses, but also promotes metabolic reprogramming and adaptions in the long-term through regulation of specific transcription factors/co-activators. We performed a whole-genome transcriptome profiling in wild-type and AMPK-deficient mouse embryonic fibroblasts (MEF) and primary hepatocytes that had been treated with two distinct classes of small-molecule AMPK activators, namely 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) or 991. This led to the identification of distinct compound-dependent gene expression signatures and to the discovery of several AMPK-regulated genes, including Flcn encoding a tumor suppressor and nutrient sensor folliculin (FLCN). Gene set enrichment and pathway analyses identified the lysosomal pathway and the associated transcription factor EB (TFEB) as key transcriptional mediator responsible for AMPK-dependent gene expression changes. AMPK-induced Flcn expression was abolished in TFEB/TFE3 double knockout MEF and the promoter activity of Flcn was profoundly reduced when its putative TFEB-binding site was mutated. Mechanistically, we have found that A...Continue Reading

Related Concepts

Gene Expression
Genes
Transcription Factor
Transcription, Genetic
Zebrafish
AICA ribonucleotide
Tumor Suppressor Genes
Hepatocyte
AMP-activated protein kinase kinase
Nutrients

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