MPI depletion enhances O-GlcNAcylation of p53 and suppresses the Warburg effect
- Icahn School of Medicine at Mount Sinai, United States
- Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, United States
- Sanford Burnham Prebys Medical Discovery Institute, United States
- New York University Abu Dhabi, United Arab Emirates
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.
Data availability
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Transcriptome profiles of surgically resected HCC tumor tissuesPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE10186).
Article and author information
Author details
Funding
National Institute of Diabetes and Digestive and Kidney Diseases (K08 DK101340)
- Jaime Chu
The Mindich Child Health and Development Institute at Mount Sinai
- Jaime Chu
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK080789)
- Kirsten C Sadler
National Institute on Alcohol Abuse and Alcoholism (R01AA018886)
- Kirsten C Sadler
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK99551)
- Hudson H Freeze
The Rocket Fund
- Hudson H Freeze
National Institute of Diabetes and Digestive and Kidney Diseases (T32DK007792)
- Charles DeRossi
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#IACUC-2015-0050) of the Icahn School of Medicine at Mount Sinai.
Copyright
© 2017, DeRossi et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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