The p53 tumor suppressor acts as a potent transcription factor in response to bombardment by a variety of cellular stresses. Its importance in maintaining genomic stability and exerting anit-proliferative effects is underscored by the fact that it is found mutated in approximately 50% of all human tumors. p53 is tightly regulated at the post-translational level though multiple modifications including ubiquitination, phosphorylation, acetylation, and neddylation. Mdm2 is a key regulator of p53 by acting as a specific E3 ligase on the protein and targeting it to the ubiquitin-proteasome pathway. Together, these two proteins provide a critical node in the cellular circuitry for countless signaling pathways to converge.


The p53 tumor suppressor exerts its anti-proliferative effects, including growth arrest, apoptosis, and cell senescence in response to various types of cellular stress (Levine, 1997). The activity of p53 as a sequence-specific transcription factor is highly regulated by post-translational modifications, protein-protein interactions, and protein stabilization (Brooks and Gu, 2003). Tight regulation of p53 is critical for maintaining cellular homeostasis. Its imperative function is underscored by the discovery of p53 mutations in over 50% of all human tumors, and those harboring wild-type p53 have strong evidence of other p53 pathway disruptions (Vousden, 2000). Indeed, Mdm2, a powerful regulator of p53, is found over expressed in approximately 5-10% of all human tumors (Juven-Gershon and Oren, 1999).

Normally at low levels in unstressed cells, p53 activity as a potent transcription factor is highly dependent on rapid and effective stabilization of the protein. The key regulator of p53 is the E3 ligase Mdm2, which ubiquitinates p53 under normal conditions and maintains the protein at low levels (Freedman et al., 1999). Upon DNA damage, however, the cell strategically targets the intricate p53-Mdm2 relationship for disruption through a variety of mechanisms. Blocking this interaction leads to quick stabilization of the protein, though the precise sequence of events leading to p53 activation remains ambiguous (Michael and Oren, 2002).

Post-translational modifications are critical events for the regulation of p53. While ubiquitination of p53 is important for regulation through the ubiquitin-proteosome pathway, other post-translational modifications such as acetylation, phosphorylation, and neddylation are important for its activity as a sequence-specific transcription factor. Several residues within p53 have been shown to be differentially phosphorylated or dephosphorylated depending on the type of DNA damage that occurs (Appella and Anderson, 2001). Further, p53 is specifically acetylated at multiple lysine residues (Lys370, Lys371, Lys372, Lys381, and Lys382) of the carboxy-terminal regulatory domain by CBP/p300 and, to a lesser extent, Lys320 by PCAF. While elucidation

Corresponding Author: Wei Gu, Berne Research Pavilion Rm 412C, Institute for Cancer Genetics, Columbia University, 1150 St. Nicholas Avenue, New York, NY 10032, Tel: (212) 851-5282 (Office), (212) 851-5285/5286 (Lab), Fax: (212) 851-5284, E-mail: [email protected]

of their precise physiological role continues, these modifications could alter the p53 protein structure to a more energetically favorable and active structure. Additionally, these modifications could serve as docking sites for other co-factors and effectors involved in p53 function.

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