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E3 ubiquitin ligase APC/C-Cdh1 accounts for the Warburg effect by linking glycolysis to cell proliferation
Open accessAbstract
Cell proliferation is known to be accompanied by activation of glycolysis. We have recently discovered that the glycolysis-promoting enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase, isoform 3 (PFKFB3), is degraded by the E3 ubiquitin ligase APC/C-Cdh1, which also degrades cell-cycle proteins. We now show in two different cell types (neoplastic and nonneoplastic) that both proliferation and aerobic glycolysis are prevented by overexpression of Cdh1 and enhanced by its silencing. Furthermore, we have coexpressed Cdh1 with PFKFB3—either wild-type or a mutant form resistant to ubiquitylation by APC/C-Cdh1—or with the glycolytic enzyme 6-phosphofructo-1-kinase and demonstrated that whereas glycolysis is essential for cell proliferation, its initiation in the presence of active Cdh1 does not result in proliferation. Our experiments indicate that the proliferative response, regardless of whether it occurs in normal or neoplastic cells, is dependent on a decrease in the activity of APC/C-Cdh1, which activates both proliferation and glycolysis. These observations have implications for cell proliferation, neoplastic transformation, and the prevention and treatment of cancer.
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“Protein levels of Pfkfb3 are low in neurons because of its constant proteasomal degradation (Herrero-Mendez et al., 2009;Almeida et al., 2010)”
From An RNA-Sequencing Transcriptome and Splicing Database of Glia, Neurons, and Vascular Cells of the Cerebral Cortex (2014) · cites this paper as Almeida et al., 2010
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Metadata
- Authors
- Almeida, A., Bolaños, J. P., & Moncada, S.
- Affiliations
- Hospital Universitario de Salamanca, Instituto de Estudios de Ciencias de la Salud de Castilla y Leon, 37007 Salamanca, Spain;
- Universidad de Salamanca (ES)
- University College London (GB)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2009-12-22
- Volume
- 107
- Issue
- 2
- Pages
- 738-741
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2818939
- OpenAlex
- W2167058369
- Cited by
- 166
- References
- 25
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 4 · 2023: 8 · 2022: 6 · 2021: 5 · 2020: 7 · 2019: 12 · 2018: 11 · 2017: 9 · 2016: 9 · 2015: 16 · 2014: 12 · 2013: 21 · 2012: 20
- FWCI
- 4.59
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (acceptedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Ministerio de Ciencia e Innovación (CSD2007-00020)
- Junta de Castilla y León
- Instituto de Salud Carlos III (2008-2011, CSD2007-00020)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- APC/C-Cdh1, E3 ubiquitin ligase, CDH1, Warburg effect, aerobic glycolysis, PFKFB3, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase, 6-phosphofructokinase, cell proliferation, ubiquitination, oncogenic transformation, cancer
- MeSH terms
- Aerobiosis, Cell Cycle, Cell Division, Gene Expression Regulation, Glycolysis, Humans, Kidney, Neuroblastoma, Phosphofructokinase-1, Tretinoin, Antigens, CD, Cadherins, Gene Expression Regulation, Neoplastic, Cell Cycle Proteins, Phosphofructokinase-2, Ubiquitin-Protein Ligases, Cell Line, Tumor
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