Figure 7

Numb and p53 relationship in T-cell development. The schematic diagram shows how the different subcellular localization patterns of Numb, depending on the presence of pre-TCR, may reciprocally regulate p53 and its own stability. Left panel illustrates DN3 thymocytes, in which the presence of the pre-TCR signal promotes PKCθ-mediated Numb phosphorylation and nuclear exclusion. This event results in the nuclear Mdm2-dependent p53 ubiquitination and degradation, finally allowing the DN3 cell survival and differentiation. Right panel shows mutant DN3 thymocytes in which the absence of pre-TCR signal does not allow PKCθ-dependent phosphorylation of Numb, which localizes mainly in the nucleus interfering with the Mdm2–p53 complex formation. This leads to proteasome-dependent degradation of Numb itself and p53 stabilization, finally resulting in both cell death and developmental block of thymocytes