The mitochondrial p53 pathway

Abstract

p53 is one of the most mutated tumor suppressors in human cancers and as such has been intensively studied for a long time. p53 is a major orchestrator of the cellular response to a broad array of stress types by regulating apoptosis, cell cycle arrest, senescence, DNA repair and genetic stability. For a long time it was thought that these functions of p53 solely rely on its function as a transcription factor, and numerous p53 target genes have been identified [1]. In the last 8 years however, a novel transcription-independent proapoptotic function mediated by the cytoplasmic pool of p53 has been revealed. p53 participates directly in the intrinsic apoptosis pathway by interacting with the multidomain members of the Bcl-2 family to induce mitochondrial outer membrane permeabilization. Our review will discuss these studies, focusing on recent advances in the field.

Fig. 1

The direct mitochondrial p53 program of apoptosis. Stress-induced mitochondrial translocation of p53 results in interactions with multidomain members (anti- and proapoptotic) of the Bcl-2 family to induce mitochondrial outer membrane permeabilization. p53 interacts with Bcl-xL and Bcl2 and neutralizes their inhibitory effects on proapoptotic Bax and Bak, which are the only members of the Bcl2 family able to oligomerize and form lipid pores on the mitochondrial outer membrane. p53 interaction with Bcl-xL also liberates proapoptotic tBid from its inhibitory complex with Bcl-xL. Moreover, p53 interacts directly with Bak, liberating it from an inhibitory complex with anti-apoptotic Mcl-1. Thus, p53 acts like a ‘super’ BH3-only protein, combining both enabling and activating BH3-only functions. p53 also interacts with Bax in a ‘hit and run’ manner, which stimulates Bax oligomerization and pore formation. In an additional cytosolic p53 pathway, p53 first transactivates Puma, which then liberates p53 from a pre-existing cytosolic Bcl-xL complex to activate monomeric Bax in the cytosol.

Fig. 2

Regulation of mitochondrial p53 translocation. The source of mitochondrially translocated p53 is a stress-stabilized pool in the cytoplasm. A two-step regulation of p53 creates a rapid-action binary switch. The product of the first step – monoubiquitinated p53, generated by basal levels of Mdm2-type E3 ligases – can undergo two opposite fates: degradation and inactivation by subsequent polyubiquitination via Mdm2 or E4-type ligases under normal conditions. Alternatively, if stress occurs, this monoubiquitinated p53 intermediate is rapidly stabilized by stress-induced disruption of the p53–Mdm2 complex and diverted to mitochondria. Upon arrival, p53 undergoes rapid deubiquitination by mitochondrial HAUSP via a stress-induced p53–HAUSP complex, which generates the apoptotically active non-ubiquitinated p53. Another major fraction of p53 translocates to the nucleus or is stabilized within to initiate its transcriptional program of target gene activation and repression.