Activation of an MDM2-specific caspase by p53 in the absence of apoptosis

Cells undergoing p53-mediated apoptosis activate caspase 3-like activities, resulting in the cleavage of the MDM2 oncoprotein and other apoptotic subs trates such as poly(ADP-ribose) polymerase, To investigate the mechanism of p53-mediated apoptosis and to determine whether cleavage of MDM2 has a pot ential role in regulating p53, we examined caspase activation and cleavage of MDM2 in a cell line undergoing p53-mediated growth arrest and delayed ap optosis, We found that in H1299 cells expressing a temperature-sensitive hu man p53, a distinct caspase activity specific for the MDM2 cleavage site DV PD is induced by p53 prior to the onset of apoptosis and loss of viability. This is accompanied by the cleavage of MDM2 but not the apoptotic substrat e poly(ADP-ribose) polymerase. The cleaved MDM2 loses the ability to promot e p53 degradation and may potentially function in a dominant-negative fashi on to stabilize p53, These results suggest that p53 activation may induce a positive feedback effect by cleavage of MDM2 through a unique caspase.