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 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.
Department of Pathology and the Center for Integrative Metabolic and Endocrine Research, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.
Yu Holly
YH
Hong
Usha S
US
Varanasi
Wenbo
W
Yang
Todd
T
Leff
D055372:AMP-Activated Protein Kinases; D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D015153:Blotting, Western; D016466:CHO Cells; D006224:Cricetinae; D004268:DNA-Binding Proteins; D019281:Dimerization; D015971:Gene Expression Regulation, Enzymologic; D017930:Genes, Reporter; D005822:Genetic Vectors; D051557:Hepatocyte Nuclear Factor 4; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000502:physiology*; D009154:Mutation; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D012694:Serine / Q000378:metabolism; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection
D004268:DNA-Binding Proteins; D051557:Hepatocyte Nuclear Factor 4; D009097:Multienzyme Complexes; D010750:Phosphoproteins; D014157:Transcription Factors; D012694:Serine; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases