@article{6a60aea6d5bf40bdb6a78aac4f986560,
title = "MPI depletion enhances O-GlcNAcylation of p53 and suppresses the Warburg effect",
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.",
author = "Nataly Shtraizent and Charles DeRossi and Shikha Nayar and Ravi Sachidanandam and Katz, {Liora S.} and Adam Prince and Koh, {Anna P.} and Adam Vincek and Yoav Hadas and Yujin Hoshida and Scott, {Donald K.} and Efrat Eliyahu and Freeze, {Hudson H.} and Sadler, {Kirsten C.} and Jaime Chu",
note = "Funding Information: Funded by National Institutes of Health [K08DK101340 to JC, 5R01DK080789 and 6R01AA018886 to KCS, R01DK99551 to HHF, T32DK007792 to CD], Gilead Sciences Research Scholars Program in Liver Disease to JC, The Rocket Fund to HHF, and the Mindich Child Health and Development Institute at Mount Sinai to JC. We thank Patrick Bradley, Matthew Nash, Chen Lu, and Louis Lin for technical support. RNA sequencing was performed at the Genomics Core Facility at the Icahn School of Medicine at Mount Sinai. TALENs were assembled by the Genetics and Model Systems Core (M McNulty, K Clark and SEkker) in the Mayo Clinic Center for Cell Signaling in Gastroenterology (NIDDK P30DK084567). 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. Publisher Copyright: {\textcopyright} Shtraizent et al.",
year = "2017",
month = jun,
day = "23",
doi = "10.7554/eLife.22477",
language = "English (US)",
volume = "6",
journal = "eLife",
issn = "2050-084X",
publisher = "eLife Sciences Publications Ltd",
}