Gene-Associated AMPK

Sci. Signal.  07 Sep 2010:
Vol. 3, Issue 138, pp. ec272
DOI: 10.1126/scisignal.3138ec272

Adenosine monophosphate–activated protein kinase (AMPK) plays a key role in the cellular response to metabolic stress. Bungard et al. show that AMPK and the upstream kinase LKB1 are activated by and important for mouse embryo fibroblasts (MEFs) to adapt to genotoxic stress and oxidative stress. Compared with wild-type MEFs, ampka–/– MEFs exhibited reduced viability in response to all of these stresses, and this was associated with reduced expression of p53-induced genes such as p21, reprimo, cyclinG, and cpt1c, suggesting that AMPK may facilitate stress-induced p53-mediated gene expression. Chromatin immunoprecipitation (ChIP) analysis of overexpressed or endogenous proteins showed that AMPK and LKB1 were associated with the p21 and cpt1c promoters in cells exposed to metabolic or genotoxic stress. AMPK immunoprecipitated from stressed cells exhibited greater in vitro kinase activity toward histone 2B (H2B), and this phosphorylation was lost if Ser36 of H2B was mutated to alanine. The abundance of H2B phosphorylated at Ser36 was greater in cells exposed to metabolic stress, and this increase was lost in cells lacking AMPK or LKB1. MEF cell lines expressing FLAG-tagged H2B with the S36A mutation exhibited induction of p53-stimulated genes and reduced viability in response to metabolic stress. Analysis of the p21 and cpt1c genes showed that metabolic stress induced an increase in H2B phosphorylated at Ser36, as well as AMPK binding, near the p53 binding site in the promoters as well as along the transcribed regions. Thus, the LKB-AMPK energy homeostasis pathway also functions in the nucleus to promote cellular adaptation to multiple forms of stress by phosphorylating H2B in target genes to promote transcription (see Hardie for commentary).

D. Bungard, B. J. Fuerth, P.-Y. Zeng, B. Faubert, N. L. Maas, B. Viollet, D. Carling, C. B. Thompson, R. G. Jones, S. L. Berger, Signaling kinase AMPK activates stress-promoted transcription via histone H2B phosphorylation. Science 329, 1201–1205 (2010). [Abstract] [Full Text]

D. G. Hardie, Targeting the core of transcription. Science 329, 1158–1159 (2010). [Summary] [Full Text]