Mdm2 has been well characterized as a negative regulator of the tumor suppressor p53. Recent studies have shown that Mdm2 is activated in response to a variety of oncogenic pathways independent of p53. Although its role as an oncogene via suppression of p53 function remains clear, growing evidence argues for p53-independent effects, as well as the remarkable possibility that Mdm2 has tumor suppressor functions in the appropriate context. Hence, Mdm2 is proving to be a key player in human cancer in its own right, and thus an important target for therapeutic intervention.

The process of cell division is highly ordered and regulated. Checkpoints exist to delay progression into the next cell cycle phase only when the previous step is fully completed. The ultimate goal is to guarantee that the two daughter cells inherit a complete and faithful copy of the genome. Checkpoints can become activated due to DNA damage, exogenous stress signals, defects during the replication of DNA, or failure of chromosomes to attach to the mitotic spindle. Abrogation of cell cycle checkpoints can result in death for a unicellular organism or uncontrolled proliferation and tumorigenesis in metazoans (Nyberg et al., 2002). The tumor suppressor p53 plays a critical role in each of these cell cycle checkpoints and is reviewed here. J. Cell. Physiol. 209: 13–20, 2006.

In response to cellular stress signals, the tumour suppressor p53 accumulates and triggers a host of antineoplastic responses. For instance, DNA damage activates two main p53‐dependent responses: cell cycle arrest and attendant DNA repair or apoptosis (cell death). It is broadly accepted that, in response to DNA damage, the function of p53 as a sequence‐specific transcription factor is crucial for tumour suppression. The molecular determinants, however, that favour the initiation of either a p53‐dependent cell cycle arrest (life) or apoptotic (death) transcriptional programme remain elusive. Gaining a clear understanding of the mechanisms controlling cell fate determination by p53 could lead to the identification of molecular targets for therapy, which could selectively sensitize cancer cells to apoptosis. This review summarizes the literature addressing this important question in the field. Special emphasis is given to the role of the p53 response element, post‐translational modifications and protein–protein interactions on cell fate decisions made by p53 in response to DNA damage.

The p53 tumor suppressor protein is a transcription factor that exerts its effects on the cell cycle via regulation of gene expression. Although the mechanism of p53-dependent transcriptional activation has been well-studied, the molecular basis for p53-mediated repression has been elusive. The E2F family of transcription factors has been implicated in regulation of cell cycle-related genes, with E2F6, E2F7, and E2F8 playing key roles in repression. In response to cellular DNA damage, E2F7, but not E2F6 or E2F8, is up-regulated in a p53-dependent manner, with p53 being sufficient to increase expression of E2F7. Indeed, p53 occupies the promoter of the E2F7 gene after genotoxic stress, consistent with E2F7 being a novel p53 target. Ablation of E2F7 expression abrogates p53-dependent repression of a subset of its targets, including E2F1 and DHFR, in response to DNA damage. Furthermore, E2F7 occupancy of the E2F1 and DHFR promoters is detected, and expression of E2F7 is sufficient to inhibit cell proliferation. Taken together, these results show that p53-dependent transcriptional up-regulation of its target, E2F7, leads to repression of relevant gene expression. In turn, this E2F7-dependent mechanism contributes to p53-dependent cell cycle arrest in response to DNA damage.