Abstract
Metabolic enzymes have been shown to function as transcriptional regulators. p53, a tumor-suppressive transcription factor, was recently found to regulate energy metabolism. These combined facts raise the possibility that metabolic enzymes may directly regulate p53 function. Here, we discover that nucleocytoplasmic malate dehydrogenase-1 (MDH1) physically associates with p53. Upon glucose deprivation, MDH1 stabilizes and transactivates p53 by binding to p53-responsive elements in the promoter of downstream genes. Knockdown of MDH1 significantly reduces binding of acetylated-p53 and transcription-active histone codes to the promoter upon glucose depletion. MDH1 regulates p53-dependent cell-cycle arrest and apoptosis in response to glucose deprivation, suggesting that MDH1 functions as a transcriptional regulator for a p53-dependent metabolic checkpoint. Our findings provide insight into how metabolism is directly linked to gene expression for controlling cellular events in response to metabolic stress.
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Abbreviations
- MDH1:
-
malate dehydrogenase-1
- GAPDH:
-
glyceraldehyde-3-phosphate dehydrogenase
- TCA:
-
tricarboxylic acid
- ChIP:
-
chromatin Immunoprecipitation
- GLUT:
-
glucose transporter
- HEK293:
-
human embryonic kidney 293
- p53-RE:
-
p53-responsive element
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Acknowledgements
We thank Dr. H-W Lee and Dr. JH Chung for invaluable materials and JW Choi for initiating the cloning of metabolic enzymes. This work was supported by KOSEF grants from the National Research Laboratory (ROA-2007-000-20002-0), the Center for Aging and Apoptosis Research at Seoul National University (R11-2002-097-050050-0) and the Center for Functional Analysis for Human Genome (3344-20060070).
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Lee, S., Kim, J., Cho, E. et al. A nucleocytoplasmic malate dehydrogenase regulates p53 transcriptional activity in response to metabolic stress. Cell Death Differ 16, 738–748 (2009). https://doi.org/10.1038/cdd.2009.5
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DOI: https://doi.org/10.1038/cdd.2009.5
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