Genes: Structure and Regulation
AMP-activated Protein Kinase Regulates HNF4α Transcriptional Activity by Inhibiting Dimer Formation and Decreasing Protein Stability*

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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 4α (HNF4α) 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 HNF4α causes diabetes in humans. Here we demonstrate that AMPK directly phosphorylates HNF4α and represses its transcriptional activity. AMPK-mediated phosphorylation of HNF4α 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 HNF4α is a downstream target of AMPK and raise the possibility that one of the effects of AMPK activation is reduced expression of HNF4α target genes.

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Present address: Dept. of Pediatrics, University of Michigan Medical School, Ann Arbor, MI 48109.