Figure 6.

Regulation of mitochondrial translocation of p53 in the cytoplasm. A two-step regulation of p53 enables the creation of a rapid-action binary switch. The product of the first step—monoubiquitylated p53, generated by basal levels of Mdm2-type E3 ligases—can undergo two diametrically opposed fates: (i) either degradation and inactivation by subsequent polyubiquitylation via Mdm2 or E4-type ligases if no stress occurs. (ii) Alternatively, if stress does occur, this monoubiquiylated intermediate p53 product is rapidly stabilized by stress-induced disruption of the p53–Mdm2 complex and diverted to mitochondria, hence becoming apoptoticically active. A stress-mediated decrease in Mdm2 levels might further contribute to the conversion of polyubiquitylated to monoubiquitylated p53 (Stommel and Wahl, 2004). In this way, the pre-existing and now stabilized pool of monoubiquitylated p53 mediates its first apoptotic response wave.