期刊
JOURNAL OF CELL BIOLOGY
卷 204, 期 5, 页码 729-745出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.201306149
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资金
- Global COE program
- Japan Society for the Promotion of Science
- Ministry of Education, Culture, Sports, Science, and Technology of Japan [20590696, 23390186]
- Japan Science and Technology Agency [8447, 5485]
- Japan Science and Technology Agency (JST) Core Research for Evolutional Science and Technology
- Grants-in-Aid for Scientific Research [25670350, 23390186, 24115004, 20590696] Funding Source: KAKEN
Despite the well-documented clinical significance of the Warburg effect, it remains unclear how the aggressive glycolytic rates of tumor cells might contribute to other hallmarks of cancer, such as bypass of senescence. Here, we report that, during oncogene- or DNA damage-induced senescence, Pak1 -mediated phosphorylation of phosphoglycerate mutase (PGAM) predisposes the glycolytic enzyme to ubiquitin-mediated degradation. We identify Mdm2 as a direct binding partner and ubiquitin ligase for PGAM in cultured cells and in vitro. Mutations in PGAM and Mdm2 that abrogate ubiquitination of PGAM restored the proliferative potential of primary cells under stress conditions and promoted neoplastic transformation. We propose that Mdm2, a downstream effector of p53, attenuates the Warburg effect via ubiquitination and degradation of PGAM.
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