Fig. 2

The “Mdm2 loops.” Depicted are two possible autoregulatory loops whose existence is supported by the data discussed in this minireview. These loops are not mutually exclusive; in fact, they most probably are integrated into each other, and are depicted as separate only for the sake of simplicity. In loop 1 (the “traditional” loop), activation of p53 is proposed to induce mdm2 transcription and production of Mdm2 protein, which then binds to p53, inactivates it, and targets it for degradation, thereby restraining excess p53 activity. Stress signals may allow p53 activation and accumulation through interfering with the inhibitory effects of Mdm2 on p53. In loop 2, augmented Mdm2 protein production (e.g., through gene amplification, translational mechanisms, etc.) is proposed to lead to down-regulation of p53 protein. This will relieve the inhibitory effect of p53 on ARF transcription and, in conjunction with the Mdm2-mediated augmentation of E2F1 activity, will result in enhanced ARF expression, and consequently in inhibition of Mdm2 function through ARF-Mdm2 protein interactions. The nonoverlapping binding sites for p53 and for ARF on the Mdm2 molecule are indicated by different shapes. See text for further details.