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

  1. Charles DeRossi
  2. Nataly Shtraizent
  3. Shikha Nayar
  4. Ravi Sachidanandam
  5. Liora S Katz
  6. Adam Prince
  7. Anna P Koh
  8. Adam Vincek
  9. Yoav Hadas
  10. Yujin Hoshida
  11. Donald K Scott
  12. Efrat Eliyahu
  13. Hudson H Freeze
  14. Kirsten C Sadler
  15. Jaime Chu  Is a corresponding author
  1. Icahn School of Medicine at Mount Sinai, United States
  2. Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, United States
  3. Sanford Burnham Prebys Medical Discovery Institute, United States
  4. 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

The following previously published data sets were used

Article and author information

Author details

  1. Charles DeRossi

    Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Nataly Shtraizent

    Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Shikha Nayar

    Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Ravi Sachidanandam

    Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Liora S Katz

    Department of Medicine, Endocrinology, Diabetes and Bone Disease, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Adam Prince

    Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Anna P Koh

    Department of Medicine, Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Adam Vincek

    Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Yoav Hadas

    Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Yujin Hoshida

    Department of Medicine, Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Donald K Scott

    Department of Medicine, Endocrinology, Diabetes and Bone Disease, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Efrat Eliyahu

    Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Hudson H Freeze

    Sanford Children's Health Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Kirsten C Sadler

    Biology Program, New York University Abu Dhabi, Abu Dhabi, United Arab Emirates
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1100-4125
  15. Jaime Chu

    Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, United States
    For correspondence
    jaime.chu@mssm.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9291-8630

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.

Reviewing Editor

  1. Ralph DeBerardinis, UT Southwestern Medical Center, United States

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.

Version history

  1. Received: October 19, 2016
  2. Accepted: June 22, 2017
  3. Accepted Manuscript published: June 23, 2017 (version 1)
  4. Version of Record published: July 3, 2017 (version 2)

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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  1. Charles DeRossi
  2. Nataly Shtraizent
  3. Shikha Nayar
  4. Ravi Sachidanandam
  5. Liora S Katz
  6. Adam Prince
  7. Anna P Koh
  8. Adam Vincek
  9. Yoav Hadas
  10. Yujin Hoshida
  11. Donald K Scott
  12. Efrat Eliyahu
  13. Hudson H Freeze
  14. Kirsten C Sadler
  15. Jaime Chu
(2017)
MPI depletion enhances O-GlcNAcylation of p53 and suppresses the Warburg effect
eLife 6:e22477.
https://doi.org/10.7554/eLife.22477

Share this article

https://doi.org/10.7554/eLife.22477

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