Regulation of transcription by AMP-activated protein kinase - Phosphorylation of p300 blocks its interaction with nuclear receptors

AMP-activated protein kinase (AMP-kinase) modulates many metabolic processe s in response to fluctuations in cellular energy status. Although most of i ts known targets are metabolic enzymes, it has been proposed that AMP-kinas e might also regulate gene expression. Here we demonstrate that the transcr iptional coactivator p300 is a substrate of AMP-kinase. Phosphorylation of p300 at serine 89 by AMP-kinase dramatically reduced its interaction, in vi tro and in vivo, with the nuclear receptors peroxisome proliferator-activat ed receptor gamma, thyroid receptor, retinoic acid receptor, and retinoid X receptor, but did not affect its interaction with the non-nuclear receptor transcription factors Ela, p53, or GATA4. These findings indicate that the AMP-kinase signaling pathway selectively modulates a subset of p300 activi ties and represent the first example of a transcriptional component regulat ed by AMP-kinase. Our results suggest a direct link between cellular energy metabolism and gene expression.