Figure 7.

Proposed working model of the synthetic lethality between PTEN and MDM2. In PTEN-wildtype cells, PTEN suppresses AKT activity, thereby limiting MDM2's inhibitory effect on p53. p53 in turn controls Bcl2 transcription. Inhibition of MDM2 in these cells has limited effect on p53-Bcl2 pathway. In PTEN-deficient cells, active AKT promotes MDM2 activity, thereby reducing p53 basal level and inhibiting p53's transactivation function. Bcl2 transcription is de-repressed and its expression is highly elevated in these cells, making the cells addicted to Bcl2. Inhibition of MDM2 in these cells activates p53, shifts Bax/Bcl2 ratio and induces mitochondria-mediated apoptosis.