Reciprocal regulation of p53 and malic enzymes modulates metabolism and senescence

Cellular senescence both protects multicellular organisms from cancer and contributes to their aging(1). The preeminent tumor suppressor p53 plays an important role in the induction and maintenance of senescence, but how p53 carries out this function remains poorly understood(1–3). Additionally, while increasing evidence supports the notion that metabolic changes underlie many cell fate decisions and p53-mediated tumor suppression, few connections between metabolic enzymes and senescence have been established. Here we describe a novel mechanism by which p53 links the functions. We show that p53 represses the expression of the tricarboxylic acid cycle (TCA cycle)-associated malic enzyme 1 (ME1) and malic enzyme 2 (ME2). Both MEs are important for NADPH production, lipogenesis, and glutamine metabolism, with ME2 having a more profound effect. Through inhibiting MEs, p53 regulates cell metabolism and proliferation. Down-regulation of ME1 and ME2 reciprocally activates p53 through distinct Mdm2 and AMPK-mediated mechanisms in a feed-forward manner, bolstering this pathway and enhancing p53 activation. Down-regulation of ME1 and ME2 also modulates the outcome of p53 activation leading to strong induction of senescence, but not apoptosis, while enforced expression of either ME suppresses senescence. Our findings define physiological functions of MEs, demonstrate a positive feedback mechanism that sustains p53 activation, and reveal a connection between metabolism and senescence mediated by p53.