The transcriptional activator and tumor suppressor protein p53 (product of the TP53 gene) was originally discovered as a protein that bound to the SV40 large T-Antigen1,5. It was later determined to be a tumor suppressor when it was found that many human tumor cells had mutations in p53, and a high percentage of p53 -/- mice developed tumors5. Approximately 50% of all human tumors have a mutation in p531,5. People with Li Fraumeni Syndrome, who carry a mutation in one p53 allele, have a >90% chance of developing cancer in their lifetime3,5. P53 earned its reputation as “Guardian of the Genome” by its crucial role in cell cycle arrest, apoptosis, and senescence in response to DNA damage3,5.
The full length human p53 protein is 393 amino acids in length. It contains two Transcriptional Transactivation Domains (TAD1, TAD2), a proline-rich domain (PPP), a large central DNA binding domain that encompasses approximately 50% of the molecule, a nuclear localization signal (NLS), and tetramerization domain (Tet), and a C-terminal regulatory domain.
The full length p53 protein is 393 amino acids in length and consists of two N-terminal transcription activation domains (TADs), a proline-rich region, a large central DNA-binding domain (DBD), a nuclear localization signal, a homo-oligomerization domain (OD), and a C-terminal domain that regulates DNA binding2,3. P53 binds DNA as a tetramer1-3, and interacts with p300 and CBP, which serve as coactivators of transcription4. Two related proteins have been identified, p63 and p73, that have similar properties as p531,5.
Activation of p53 can be triggered by a variety of cellular stresses including DNA damage, hypoxia, nutrient deprivation, cell-cell contact, interference with ribosome biogenesis, overexpression of oncogenes (e.g. c-myc or Ras), or the presence of viruses 4. Each of these activation signals has a unique set of upstream and downstream pathways that regulate the activity of p53.
Under permissive growth conditions, growth factor signals act through the kinase AKT to stabilize and activate MDM2 and MDMX, which in turn drive the degradation of p53, leaving cellular levels of p53 low. In the absence of high levels of p53 cells are able to progress through the cell cycle, divide, and proliferate.
In presence of DNA damage the serine/threonine kinase ATM is activated, which phosphorylates MDM2, MDMX, and p53. Phosphorylation of MDM2 and MDMX results in the stabilization and activation of p53, leading to transcription of downstream genes involved in cell cycle arrest (p21, GADD45) and apoptosis (BAX, PUMA, and NOXA).
The key upstream regulators of p53 stability and activity in response to DNA damage are the serine/threonine kinase ATM4,7, MDM2, and MDMX (MDM4)1,4,5,7. Under normal conditions, p53 levels are low due to the action of MDM2 and MDMX1,4,5 MDM2 associates with p53 and targets it for degradation in the cytoplasm by virtue of its innate E3 ubiquitin ligase activity1,4,5,7. MDMX stabilizes MDM2 and helps drive the degradation of p53. In the presence of DNA damage, ATM phosphorylates MDM2 and releases p53 which then activates transcription of p21, a cyclin-dependent kinase inhibitor, leading to cell cycle arrest at the G1/S stage1,4,5,7. P53 also activates the transcription of Gadd45a which augments cell cycle arrest3. Under the appropriate conditions, activated p53 can drive cells to apoptosis by activating transcription of the Bcl family genes Bax, Puma, and Noxa1,3.
P53 is an attractive target for development of novel therapeutics1,6. While replacement of a wild type p53 gene may be possible in some cases, a more attractive approach is the development of small molecule agents that can disrupt MDM2—p53 interaction or stabilize mutant forms of p53 in which the functional domains are still intact. Both approaches are currently being pursued6.
Below is the entire list of targets involved in p53 research. Can’t find what you are looking for? Bethyl offers a custom antibody service.