AMP-activated protein kinase regulates HNF4alpha transcriptional activity by inhibiting dimer formation and decreasing protein stability

AMP-activated protein kinase (AMPK) is the central component of a cellular signaling system that regulates multiple metabolic enzymes and pathways in response to reduced intracellular energy levels. The transcription factor hepatic nuclear factor 4alpha (HNF4alpha) is an orphan nuclear receptor that...

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Bibliographic Details
Published in:The Journal of biological chemistry 2003-07, Vol.278 (30), p.27495-27501
Main Authors: Hong, Yu Holly, Varanasi, Usha S, Yang, Wenbo, Leff, Todd
Format: Article
Language:English
Subjects:
Alleles
Amino Acid Sequence
AMP-Activated Protein Kinases
Animals
Binding Sites
Blotting, Western
CHO Cells
Cricetinae
Dimerization
DNA-Binding Proteins
Gene Expression Regulation, Enzymologic
Genes, Reporter
Genetic Vectors
Hepatocyte Nuclear Factor 4
Molecular Sequence Data
Multienzyme Complexes - physiology
Mutation
Phosphoproteins - metabolism
Phosphorylation
Plasmids - metabolism
Promoter Regions, Genetic
Protein Structure, Tertiary
Protein-Serine-Threonine Kinases - physiology
Sequence Homology, Amino Acid
Serine - metabolism
Time Factors
Transcription Factors - metabolism
Transcription, Genetic
Transfection
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Summary:AMP-activated protein kinase (AMPK) is the central component of a cellular signaling system that regulates multiple metabolic enzymes and pathways in response to reduced intracellular energy levels. The transcription factor hepatic nuclear factor 4alpha (HNF4alpha) is an orphan nuclear receptor that regulates the expression of genes involved in energy metabolism in the liver, intestine, and endocrine pancreas. Inheritance of a single null allele of HNF4alpha causes diabetes in humans. Here we demonstrate that AMPK directly phosphorylates HNF4alpha and represses its transcriptional activity. AMPK-mediated phosphorylation of HNF4alpha on serine 304 had a 2-fold effect, reducing the ability of the transcription factor to form homodimers and bind DNA and increasing its degradation rate in vivo. These results demonstrate that HNF4alpha is a downstream target of AMPK and raise the possibility that one of the effects of AMPK activation is reduced expression of HNF4alpha target genes.
ISSN:0021-9258