One of the distinctive metabolic features in cancerous cells is the tendency to consume high amounts of glucose in lactate production. The enhancement of glycolysis is clinically established and is known as the Warburg effect, while its post-transcriptional regulation is not clear. The conversion of 3-phosphoglycerate to 2-phosphoglycerate in the glycolytic pathway is catalyzed by phosphoglycerate mutase (PGAM), which is upregulated in many human cancer cells. In this review, we focus on the recent observations in the regulation of PGAM. We recently identified Mdm2 as a ubiquitin ligase for PGAM. Serine 118 residue in PGAM is phosphorylated by Pak1 kinase under senescence-inducing stress, which triggers the ubiquitination of PGAM. Oncogenic stimuli such as Ras-G12V provoke premature senescence, accompanied by the proteolytic degradation of PGAM by wild type Mdm2, while the oncogenic combination such as Ras-G12V+Mdm2-M459I transforms primary cells by stabilization of PGAM. Thus, Mdm2 functions as a tumor suppressor to attenuate the Warburg effect.