Senescence-inducing stress promotes proteolysis of phosphoglycerate mutase via ubiquitin ligase Mdm2

• DOI: 10.1083/jcb.201306149
• Publication Date: 2014-02-25T02:38:10Z
• Authors: Takumi Mikawa; Takeshi Maruyama; Koji Okamoto; Hitoshi Nakagama; Matilde E. Lleonart; Takeshi Tsusaka; Kousuke Hori; Itsuo Murakami; Taisuke Izumi; Akifumi Takaori-K...; Masayuki Yokode; Gordon Peters; David Beach; Hiroshi Kondoh
• Keywords: Phosphoglycerate mutase; Warburg Effect; Senescence; Proteolysis

Despite the well-documented clinical significance of Warburg effect, it remains unclear how aggressive glycolytic rates tumor cells might contribute to other hallmarks cancer, such as bypass senescence. Here, we report that, during oncogene- or DNA damage–induced senescence, Pak1-mediated phosphorylation phosphoglycerate mutase (PGAM) predisposes enzyme ubiquitin-mediated degradation. We identify Mdm2 a direct binding partner and ubiquitin ligase for PGAM in cultured vitro. Mutations that abrogate ubiquitination restored proliferative potential primary under stress conditions promoted neoplastic transformation. propose Mdm2, downstream effector p53, attenuates effect via degradation PGAM.