Mechanism of action of PS-341–induced apoptosis.

PS-341 induces the up-regulation of p53 by the inhibition of UPP. Up-regulated p53 in turn induces MDM2 protein, which binds to p53 as a negative regulator of p53. JNK activates caspase-8 and caspase-3. Activation of caspase-3 induces DNA damage, which induces p53 (Ser15) phosphorylation. Phosphorylation of p53 by DNA-PKcs, ATM/ATR, or both and degradation of MDM2 by caspase-3 trigger the dissociation of MDM2/p53 binding. Furthermore, the activation of caspase-3 cleaves DNA-PKcs and ATM/ATR proteins, resulting in impaired DNA repair.