PUBLICATION
MPI depletion enhances O-GlcNAcylation of p53 and suppresses the Warburg effect
- Authors
- DeRossi, C., Shtraizent, N., Nayar, S., Sachidanandam, R., Katz, L.S., Prince, A., Koh, A.P., Vincek, A., Hadas, Y., Hoshida, Y., Scott, D.K., Eliyahu, E., Freeze, H.H., Sadler, K.C., Chu, J.
- ID
- ZDB-PUB-170624-2
- Date
- 2017
- Source
- eLIFE 6: (Journal)
- Registered Authors
- Chu, Jaime, DeRossi, Charles, Nayar, Shikha, Sadler Edepli, Kirsten C., Shtraizent, Nataly
- Keywords
- cancer biology, cell biology, human, mouse, zebrafish
- MeSH Terms
-
- Acetylglucosamine/metabolism*
- Animals
- Cell Line, Tumor
- Fructosephosphates/metabolism
- Glycolysis
- Humans
- Mannose-6-Phosphate Isomerase/metabolism*
- Protein Processing, Post-Translational*
- Tumor Suppressor Protein p53/metabolism*
- Zebrafish/embryology
- Zebrafish Proteins/metabolism*
- PubMed
- 28644127 Full text @ Elife
Citation
DeRossi, C., Shtraizent, N., Nayar, S., Sachidanandam, R., Katz, L.S., Prince, A., Koh, A.P., Vincek, A., Hadas, Y., Hoshida, Y., Scott, D.K., Eliyahu, E., Freeze, H.H., Sadler, K.C., Chu, J. (2017) MPI depletion enhances O-GlcNAcylation of p53 and suppresses the Warburg effect. eLIFE. 6.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping