MPI depletion enhances O-GlcNAcylation of p53 and suppresses the Warburg effect

Nataly Shtraizent, Charles DeRossi, Shikha Nayar, Ravi Sachidanandam, Liora S. Katz, Adam Prince, Anna P. Koh, Adam Vincek, Yoav Hadas, Yujin Hoshida, Donald K. Scott, Efrat Eliyahu, Hudson H. Freeze, Kirsten C. Sadler, Jaime Chu

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Rapid cellular proliferation in early development and cancer depends on glucose metabolism to fuel macromolecule biosynthesis. Metabolic enzymes are presumed regulators of this glycolysis-driven metabolic program, known as the Warburg effect; however, few have been identified. We uncover a previously unappreciated role for Mannose phosphate isomerase (MPI) as a metabolic enzyme required to maintain Warburg metabolism in zebrafish embryos and in both primary and malignant mammalian cells. The functional consequences of MPI loss are striking: glycolysis is blocked and cells die. These phenotypes are caused by induction of p53 and accumulation of the glycolytic intermediate fructose 6-phosphate, leading to engagement of the hexosamine biosynthetic pathway (HBP), increased O-GlcNAcylation, and p53 stabilization. Inhibiting the HBP through genetic and chemical methods reverses p53 stabilization and rescues the Mpi-deficient phenotype. This work provides mechanistic evidence by which MPI loss induces p53, and identifies MPI as a novel regulator of p53 and Warburg metabolism.

Original languageEnglish (US)
Article numbere22477
JournaleLife
Volume6
DOIs
StatePublished - Jun 23 2017
Externally publishedYes

Fingerprint

Isomerases
Mannose
Phosphates
Metabolism
Hexosamines
Biosynthetic Pathways
Glycolysis
Stabilization
Phenotype
Biosynthesis
Zebrafish
Enzymes
Macromolecules
Embryonic Structures
Cells
Cell Proliferation
Glucose
mannose isomerase
Neoplasms

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Cite this

Shtraizent, N., DeRossi, C., Nayar, S., Sachidanandam, R., Katz, L. S., Prince, A., ... Chu, J. (2017). MPI depletion enhances O-GlcNAcylation of p53 and suppresses the Warburg effect. eLife, 6, [e22477]. https://doi.org/10.7554/eLife.22477

MPI depletion enhances O-GlcNAcylation of p53 and suppresses the Warburg effect. / Shtraizent, Nataly; DeRossi, Charles; Nayar, Shikha; Sachidanandam, Ravi; Katz, Liora S.; Prince, Adam; Koh, Anna P.; Vincek, Adam; Hadas, Yoav; Hoshida, Yujin; Scott, Donald K.; Eliyahu, Efrat; Freeze, Hudson H.; Sadler, Kirsten C.; Chu, Jaime.

In: eLife, Vol. 6, e22477, 23.06.2017.

Research output: Contribution to journalArticle

Shtraizent, N, DeRossi, C, Nayar, S, Sachidanandam, R, Katz, LS, Prince, A, Koh, AP, Vincek, A, Hadas, Y, Hoshida, Y, Scott, DK, Eliyahu, E, Freeze, HH, Sadler, KC & Chu, J 2017, 'MPI depletion enhances O-GlcNAcylation of p53 and suppresses the Warburg effect', eLife, vol. 6, e22477. https://doi.org/10.7554/eLife.22477
Shtraizent N, DeRossi C, Nayar S, Sachidanandam R, Katz LS, Prince A et al. MPI depletion enhances O-GlcNAcylation of p53 and suppresses the Warburg effect. eLife. 2017 Jun 23;6. e22477. https://doi.org/10.7554/eLife.22477
Shtraizent, Nataly ; DeRossi, Charles ; Nayar, Shikha ; Sachidanandam, Ravi ; Katz, Liora S. ; Prince, Adam ; Koh, Anna P. ; Vincek, Adam ; Hadas, Yoav ; Hoshida, Yujin ; Scott, Donald K. ; Eliyahu, Efrat ; Freeze, Hudson H. ; Sadler, Kirsten C. ; Chu, Jaime. / MPI depletion enhances O-GlcNAcylation of p53 and suppresses the Warburg effect. In: eLife. 2017 ; Vol. 6.
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