Signaling Kinase AMPK Activates Stress-Promoted Transcription via Histone H2B Phosphorylation

Department of Cellular and Developmental Biology, University of Pennsylvania Medical School, Philadelphia, PA 19104, USA.
Science (Impact Factor: 33.61). 09/2010; 329(5996):1201-5. DOI: 10.1126/science.1191241
Source: PubMed


The mammalian adenosine monophosphate–activated protein kinase (AMPK) is a serine-threonine kinase protein complex that is
a central regulator of cellular energy homeostasis. However, the mechanisms by which AMPK mediates cellular responses to metabolic
stress remain unclear. We found that AMPK activates transcription through direct association with chromatin and phosphorylation
of histone H2B at serine 36. AMPK recruitment and H2B Ser36 phosphorylation colocalized within genes activated by AMPK-dependent pathways, both in promoters and in transcribed regions.
Ectopic expression of H2B in which Ser36 was substituted by alanine reduced transcription and RNA polymerase II association to AMPK-dependent genes, and lowered cell
survival in response to stress. Our results place AMPK-dependent H2B Ser36 phosphorylation in a direct transcriptional and chromatin regulatory pathway leading to cellular adaptation to stress.

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Available from: Brandon Faubert, Oct 29, 2015
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    • "Indeed, we found that adenosine induces AMPK phosphorylation in CD39 À T cells (Figure 7F ). In addition to activating p53, AMPK regulates transcription of stress-inducible genes by directly promoting histone H2B phosphorylation (Bungard et al., 2010). These direct transcriptional activities of AMPK do not include PUMA, which may explain why PUMA was not different between CD39 À and CD39 + T cells. "
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    • "For all of the three subunits, α subunit is the most important. Activation of AMPK follows conformational change of α subunit and phosphorylation at Thr172 [22]. The phosphorylation is induced by the upstream signal molecule such as liver kinase B1 (LKB1) [23]. "
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    ABSTRACT: Adenosine monophosphate-activated protein kinase (AMPK) acts as a master mediator of metabolic homeostasis. It is considered as a significant millstone to treat metabolic syndromes including obesity, diabetes, and fatty liver. It can sense cellular energy or nutrient status by switching on the catabolic pathways. Investigation of AMPK has new findings recently. AMPK can inhibit cell growth by the way of autophagy. Thus AMPK has become a hot target for small molecular drug design of tumor inhibition. Activation of AMPK must undergo certain extent change of the structure. Through the methods of structure-based virtual screening and molecular dynamics simulation, we attempted to find out appropriate small compounds from the world's largest TCM Database@Taiwan that had the ability to activate the function of AMPK. Finally, we found that two TCM compounds, eugenyl_beta-D-glucopyranoside and 6-O-cinnamoyl-D-glucopyranose, had the qualification to be AMPK agonist.
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    • "David et al. reported that AMPK could activate transcription through direct association with chromatin and phosphorylation of histone H2B at serine 36, and it is important for cellular adaptation to stress (39). To determine if AMPK can regulate other histone epigenetic modification such as histone O-GlcNAcylation, we treated the MEFs with AICAR, a well-known AMPK activator, and then examined histone modifications by western blotting. "
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    ABSTRACT: Histone H2B O-GlcNAcylation is an important post-translational modification of chromatin during gene transcription. However, how this epigenetic modification is regulated remains unclear. Here we found that the energy-sensing adenosine-monophosphate-activated protein kinase (AMPK) could suppress histone H2B O-GlcNAcylation. AMPK directly phosphorylates O-linked β-N-acetylglucosamine (O-GlcNAc) transferase (OGT). Although this phosphorylation does not regulate the enzymatic activity of OGT, it inhibits OGT–chromatin association, histone O-GlcNAcylation and gene transcription. Conversely, OGT also O-GlcNAcylates AMPK and positively regulates AMPK activity, creating a feedback loop. Taken together, these results reveal a crosstalk between the LKB1-AMPK and the hexosamine biosynthesis (HBP)-OGT pathways, which coordinate together for the sensing of nutrient state and regulation of gene transcription.
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