Wednesday, July 11, 2012


p53 is a 44 kilodalton protein encoded by the TP53 gene. It is a tumor suppressor with crucial roles in both the induction of apoptosis and the arrest of cell cycle. Consequently, at least half of all proliferating tumor cells contain one or two mutated copies of TP53. While the protein has a mass of 44 kilodaltons, the presence of numerous proline residues impairs linearization of the protein during SDS-PAGE, so p53 migrates more slowly than expected and has an apparent mass of 53 kilodaltons in western blots. Isoforms of p53 are found in nearly all mammalian tissues.

The expression and localization of p53 within a cell can be visualized through immunofluorescence using a polyclonal or site-specific monoclonal p53 antibody. While p53 is primarily localized in the nucleus when active, it is transported into the cytoplasm by the binding protein, MDM2, and may be faintly visible there when inactive. In some forms of cancer, including breast cancers and neuroblastomas, p53 aggregates in small cytoplasmic puncta, where it is "sequestered" from both degradation and its normal regulatory role within the nucleus.

When it is allowed to aggregate within the nucleus, p53 acts as a potent mediator of cell cycle, apoptosis, and DNA repair. A central DNA-binding domain is positively-charged with a zinc moiety and several arginine residues. This allows for the upregulation of repair genes and the suppresson of oncogenes such as LMO3. Over 200 genes are transcriptionally regulated by p53, and numerous nongenomic sites contain the p53 consensus sequence. During times of cellular stress, p53 arrests the cell cycle in the G1 phase until the cell's DNA has been repaired or the source of stress has been relieved. p53 halts the cell cycle by interacting with members of the E2F family of proteins and preventing progression through G1-S phase "checkpoints". If p53 is not inactivated, the cell becomes functionally senescent.

(Image from: The p53 response)

The role of p53 in apoptotic signaling primarily involves interaction with members of the ASPP protein family. The introduction of DNA damage or oncogene upregulation to a cell results in ASPP1 and ASPP2 expression. In humans the C-terminals of these proteins bind to p53. This activates the mitochondrial apoptotic pathway by activating PUMA (p53 upregulated modulator of apoptosis) and inhibiting activity of the antiapoptotic Bcl-2 protein. Conversely, expression of the iASPP (inhibitory ASPP) competes with and prevents ASPP1 and ASPP2 binding to p53 and is therefore antiapoptotic.

Perhaps the most well-researched aspect of p53 activity is its role as a tumor suppressor. This suppression is largely through p53's ability to halt cell division and induce apoptosis in cells (as in the case of E2F and ASPP proteins, respectively). p53 also interacts with YB1 (Y-box binding protein 1), which facilitates proliferation and inhibits apoptosis by downregulating p53 expression. Mutated forms of p53, including the forms seen in many cancer types, alter the interaction with YB1, causing YB1 to build up in the nucleus and inhibit p53 activity indefinitely, leading to proliferation and tumorigenesis. Thus, p53 is a potent tumor suppressor and its inactivation facilitates the development of tumors. Indeed, the anti-tumor effects of p53 are essential for long-term survival. The inactivation of a single parental copy of TP53 causes Li-Fraumeni syndrome, an autosomal dominant disorder characterized by the early onset of multiple forms of malignant cancer, especially sarcomas.

p53 expression is primarily regulated through the activity of the protein MDM2, which binds to the trans-activation domain at the N-terminal of the p53 protein. In normal cells, p53 has a half-life of under thirty minutes due to MDM2 binding, which exports p53 from the nucleus and marks it for ubiquitination and eventual proteolysis. However, during times of cell stress the MDM2 mechanism becomes dysregulated, leading to an increase in p53 protein levels. For instance, DNA damage activates DNA-damage kinases that lead to both auto-deregulation of MDM2 and the phosphorylation of p53, which disrupts MDM2 binding.

In cancer cells, p53 is often suppressed through the activation of cyclooxygenase-2 (COX-2), which inhibits apoptosis in these cells by phosphorylating MDM2 at ser166 to stimulate its degration of p53. COX inhibitors can enhance chemotherapy-induced apoptosis by downregulating MDM2. This results in slower p53 degradation and a gradual buildup of nuclear p53 levels, which enhances both the cell cycle arrest and apoptotic signaling mediated by the protein. Similarly, MDM2 antagonists such as Nutlin-3a increase the effectiveness of chemotherapeutic drugs by disinhibiting endogenous p53 activity.

Many types of cellular stress alter the localization of p53. This includes the administration of ionizing radiation, oxidative stress, hypoxia, and oncogene expression. These forms of stress cause a rapid upregulation and transnucleation of the p53 protein that can be visualized using a p53 antibody. Similarly, the myriad interactions of p53 with its DNA binding sites have been identified through chromatin immunoprecipitation using p53 antibodies on the homogenates of lightly-fixed tissue. Recent research indicates that p53 contains multiple isoforms created from splice variants of the TP53 gene that have varying affinities for MDM2 and can be identified through western blotting (in instances where the splice has a different protein length) or using a monoclonal antibody (where the epitope is absent in one of the isoforms). The presence of such isoforms may be indicative of certain forms of cancer.


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