2. Academic Validation
  3. Transient APC/C inactivation by mTOR boosts glycolysis during cell cycle entry

Transient APC/C inactivation by mTOR boosts glycolysis during cell cycle entry

  • Nature. 2025 Jul 30. doi: 10.1038/s41586-025-09328-w.
Debasish Paul 1,  Derek L Bolhuis 2 3,  Hualong Yan 1,  Sudipto Das 4,  Xia Xu 4,  Christina C Abbate 5,  Lisa M M Jenkins 6,  Michael J Emanuele 7,  Thorkell Andresson 4,  Jing Huang 1,  John G Albeck 5,  Nicholas G Brown 3 7,  Steven D Cappell 8
Affiliations

Affiliations

  • 1 Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
  • 2 Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC, USA.
  • 3 Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.
  • 4 Protein Characterization Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
  • 5 Department of Molecular and Cellular Biology, University of California, Davis, CA, USA.
  • 6 Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
  • 7 Department of Pharmacology, University of North Carolina, Chapel Hill, NC, USA.
  • 8 Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA. steven.cappell@nih.gov.
PMID: 40739344 DOI: 10.1038/s41586-025-09328-w
Abstract

Mammalian cells entering the cell cycle favour glycolysis to rapidly generate ATP and produce the biosynthetic intermediates that are required for rapid biomass accumulation1. Simultaneously, the ubiquitin-ligase anaphase-promoting complex/cyclosome and its coactivator CDH1 (APC/CCDH1) remains active, allowing origin licensing and blocking premature DNA replication. Paradoxically, glycolysis is reduced by APC/CCDH1 through the degradation of key glycolytic Enzymes2, raising the question of how cells coordinate these mutually exclusive events to ensure proper cell division. Here we show that cells resolve this paradox by transiently inactivating the APC/C during cell cycle entry, which allows a transient metabolic shift favouring glycolysis. After mitogen stimulation, rapid mTOR-mediated phosphorylation of the APC/C adapter protein CDH1 at the amino terminus causes it to partially dissociate from the APC/C. This partial inactivation of the APC/C leads to the accumulation of PFKFB3, a rate-limiting enzyme for glycolysis, promoting a metabolic shift towards glycolysis. Delayed accumulation of Phosphatase activity later removes CDH1 phosphorylation, restoring full APC/C activity, and shifting cells back to favouring Oxidative Phosphorylation. Thus, cells coordinate the simultaneous demands of cell cycle progression and metabolism through an incoherent feedforward loop, which transiently inhibits APC/C activity to generate a pulse of glycolysis that is required for mammalian cell cycle entry.

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Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-134904
    mTORC1-Selective Inhibitor