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p53 is regulated by aerobic glycolysis in cancer cells by the CtBP family of NADH-dependent transcriptional regulators

p53 is regulated by aerobic glycolysis in cancer cells by the CtBP family of NADH-dependent transcriptional regulators
p53 is regulated by aerobic glycolysis in cancer cells by the CtBP family of NADH-dependent transcriptional regulators
High rates of glycolysis in cancer cells are a well-established characteristic of many human tumors, providing rapidly proliferating cancer cells with metabolites that can be used as precursors for anabolic pathways. Maintenance of high glycolytic rates depends upon the lactate dehydrogenase–catalyzed regeneration of NAD+ from GAPDH-generated NADH, because an increased NADH:NAD+ ratio inhibits GAPDH. Here, using human breast cancer cell models, we identified a pathway in which changes in the extra-mitochondrial free NADH:NAD+ ratio signaled through the CtBP family of NADH-sensitive transcriptional regulators to control the abundance and activity of p53. NADH-free forms of CtBPs cooperated with the p53-binding partner HDM2 to suppress p53 function, and loss of these forms in highly glycolytic cells resulted in p53 accumulation. We propose that this pathway represents a “glycolytic stress response” in which the initiation of a protective p53 response by an increased NADH:NAD+ ratio enables cells to avoid cellular damage caused by mismatches between metabolic supply and demand.
1937-9145
Birts, Charles
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Banerjee, Arindam
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Darley, Matthew
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Dunlop, Charles
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Nelson, Sarah
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Nijjar, Sharandip
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Parker, Rachel
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West, Jonathan
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Tavassoli, Ali
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Rose-Zerilli, Matthew
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Blaydes, Jeremy
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Birts, Charles
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Banerjee, Arindam
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Darley, Matthew
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Dunlop, Charles
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Nelson, Sarah
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Nijjar, Sharandip
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Parker, Rachel
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West, Jonathan
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Tavassoli, Ali
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Rose-Zerilli, Matthew
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Blaydes, Jeremy
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Birts, Charles, Banerjee, Arindam, Darley, Matthew, Dunlop, Charles, Nelson, Sarah, Nijjar, Sharandip, Parker, Rachel, West, Jonathan, Tavassoli, Ali, Rose-Zerilli, Matthew and Blaydes, Jeremy (2020) p53 is regulated by aerobic glycolysis in cancer cells by the CtBP family of NADH-dependent transcriptional regulators. Science Signaling, 13 (630), [eaau9529]. (doi:10.1126/scisignal.aau9529).

Record type: Article

Abstract

High rates of glycolysis in cancer cells are a well-established characteristic of many human tumors, providing rapidly proliferating cancer cells with metabolites that can be used as precursors for anabolic pathways. Maintenance of high glycolytic rates depends upon the lactate dehydrogenase–catalyzed regeneration of NAD+ from GAPDH-generated NADH, because an increased NADH:NAD+ ratio inhibits GAPDH. Here, using human breast cancer cell models, we identified a pathway in which changes in the extra-mitochondrial free NADH:NAD+ ratio signaled through the CtBP family of NADH-sensitive transcriptional regulators to control the abundance and activity of p53. NADH-free forms of CtBPs cooperated with the p53-binding partner HDM2 to suppress p53 function, and loss of these forms in highly glycolytic cells resulted in p53 accumulation. We propose that this pathway represents a “glycolytic stress response” in which the initiation of a protective p53 response by an increased NADH:NAD+ ratio enables cells to avoid cellular damage caused by mismatches between metabolic supply and demand.

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Birts et al 2020 Sci Sig Author Accepted with Figures - Accepted Manuscript
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Submitted date: 2019
Accepted/In Press date: 21 April 2020
e-pub ahead of print date: 5 May 2020
Published date: 5 May 2020

Identifiers

Local EPrints ID: 440537
URI: http://eprints.soton.ac.uk/id/eprint/440537
ISSN: 1937-9145
PURE UUID: 7e08e0a7-0663-4df5-851b-f2e76842e64d
ORCID for Charles Birts: ORCID iD orcid.org/0000-0002-0368-8766
ORCID for Arindam Banerjee: ORCID iD orcid.org/0000-0003-2292-4936
ORCID for Jonathan West: ORCID iD orcid.org/0000-0002-5709-6790
ORCID for Ali Tavassoli: ORCID iD orcid.org/0000-0002-7420-5063
ORCID for Matthew Rose-Zerilli: ORCID iD orcid.org/0000-0002-1064-5350
ORCID for Jeremy Blaydes: ORCID iD orcid.org/0000-0001-8525-0209

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Date deposited: 07 May 2020 16:30
Last modified: 18 Feb 2021 17:19

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Contributors

Author: Charles Birts ORCID iD
Author: Matthew Darley
Author: Charles Dunlop
Author: Sarah Nelson
Author: Sharandip Nijjar
Author: Rachel Parker
Author: Jonathan West ORCID iD
Author: Ali Tavassoli ORCID iD
Author: Jeremy Blaydes ORCID iD

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