The p53 Tumor Suppressor

Mutations of the p53 tumor supressor are among the most frequently observed genetic alterations found in cancer. Cellular p53 levels increase in response to DNA damage, resulting in either cell-cycle arrest or cell death via apoptosis. Most alterations of p53 in tumors are associated with the deletion of one allele combined with mutation of the second allele. The majority of the mutations in p53 map to a central 200 amino acid region (the core domain) that contains the sequence-specific DNA binding activity of the protein.

[Enlarge Image] p53 Core Domain Bound to DNA

The core domain of p53 in complex with DNA bearing the consensus p53-binding site is shown here. DNA-binding by p53 is essential to its activity as a transcriptional activator of the Cdk inhibitor p21 (Cip1). The 6 most frequently mutated amino acids of p53 are indicated in yellow.

[Enlarge Image] Tetramerization Domain of p53

The tetramerization domain of p53 appears here. Oligomerization of p53 is required for in vivo p53 activity and contributes to the dominant-negative effect of some p53 mutants.

[Enlarge Image] MDM2 Bound to p53 Transactivation Domain Peptide

MDMD2 is a cellular inhibitor of p53 activity via binding to the transactivation domain of p53, reducing the latter's ability to activate transcription of target genes and also targeting p53 for ubiquitin-mediated degradation. MDM2 levels are amplified in certain tumors and contribute to p53. We determined the structure of MDM2 (shown in cyan) in complex with a peptide from the transactivation domain of p53 (yellow). This structure suggested that the MDM2-p53 interface may be amenable to inhibition by small molecule compounds that can help restore the function of the p53 pathway in a subset of cancers.

[Enlarge Image] 53BP2 Bound to the Core Domain of p53

53BP2 was identified in a yeast 2-hybrid screen as a p53-binding protein. 53BP2 can inhibit the binding of p53 to DNA via interaction with the DNA-binding surface of the p53 core domain. 53BP2 binding to p53 is reduced by mutants that disrupt the DNA-binding activity of the p53 core domain.

[Enlarge Image] Complex between E6AP (E3) and UbcH7 (E2) Proteins

Levels of p53 in the cell are regulated to a large extent by the degradation of p53 mediated by the MDM2 protein. In cervical cancer, which is associated with the human papilloma virus, the viral E6 protein promotes the ubiquitin-mediated degradation of p53 in conjunction with the cellular E6AP protein. Intermediate steps in the transfer of ubiquitin from the ubiquitin-activating enzyme (E1) to the p53 substrate involve transfer of ubiquitin from E1 to E2, and from E2 to E3. Here, we show a complex of an E2 protein (UbcH7, in cyan) and the E3 protein (E6AP, in red and green).