title: Senescence-inducing stress promotes proteolysis of phosphoglycerate mutase via ubiquitin ligase Mdm2.
abstract: 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.
authors.affiliation: Department of Geriatric Medicine and 2 Department of Hematology/Oncology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Takumi
authors.initials: T
authors.lastname: Mikawa
authors.forename: Takeshi
authors.initials: T
authors.lastname: Maruyama
authors.forename: Koji
authors.initials: K
authors.lastname: Okamoto
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Nakagama
authors.forename: Matilde E
authors.initials: ME
authors.lastname: Lleonart
authors.forename: Takeshi
authors.initials: T
authors.lastname: Tsusaka
authors.forename: Kousuke
authors.initials: K
authors.lastname: Hori
authors.forename: Itsuo
authors.initials: I
authors.lastname: Murakami
authors.forename: Taisuke
authors.initials: T
authors.lastname: Izumi
authors.forename: Akifumi
authors.initials: A
authors.lastname: Takaori-Kondo
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yokode
authors.forename: Gordon
authors.initials: G
authors.lastname: Peters
authors.forename: David
authors.initials: D
authors.lastname: Beach
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kondoh
mesh_terms: D000818:Animals; D002460:Cell Line; D016922:Cellular Senescence; D004249:DNA Damage; D015536:Down-Regulation; D045325:HCT116 Cells; D057809:HEK293 Cells; D019073:HT29 Cells; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D010736:Phosphoglycerate Mutase / Q000378:metabolism*; D010766:Phosphorylation; D059748:Proteolysis; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism / Q000502:physiology*; D013312:Stress, Physiological; D025801:Ubiquitin / Q000378:metabolism; D054462:p21-Activated Kinases / Q000378:metabolism / Q000502:physiology
chemical_list: D025801:Ubiquitin; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C515903:PAK1 protein, human; D054462:p21-Activated Kinases; D010736:Phosphoglycerate Mutase