Cytosolic and mitochondrial p53 apoptotic pathways. In the cytosolic p53 apoptotic pathway, nuclear p53 induces Puma expression, which in turn releases cytosolic p53 held inactive in the cytoplasm through binding to Bcl-XL. Then, cytosolic p53 induces Bax oligomerization and mitochondrial translocation. Accumulation of p53 in the cytosol as a consequence of normal intracellular transport or stable monoubiquitination is the major source for mitochondrial p53. In the mitochondria, p53 induces Bax and Bak oligomerization, antagonizes the Bcl-2 and Bcl-XL antiapoptotic effect, and forms a complex with cyclophilin D in the mitochondrial inner membrane. These changes result in marked disruption of mitochondrial membranes and subsequent release of both soluble and insoluble apoptogenic factors. MPT, mitochondrial permeability transition; U, ubiquitin.