Approaches for Targeting p53. The figure depicts 3 classes of p53-targeting compounds under study and their implications in cancer therapeutics.
As its moniker "guardian of the genome" suggests, p53 has become recognized as one of the most important cancer-related molecules in the cell. As yet, p53-based research has not had a significant impact on cancer management. However, researchers continue to uncover complexities of and roles for the p53 pathway in both normal and cancerous cells, and the future for p53-targeted therapies is looking brighter than ever.A Major Barrier to Tumorigenesis
TP53, the gene encoding the human p53 protein, was discovered through the combined efforts of a number of different researchers in the late 1970s, but it wasn't until the 1990s that its vital role as a tumor suppressor was uncovered. It was this discovery that led to its being named "Molecule of the Year" by Science magazine in 1993.
p53 is a transcription factor that, upon activation, moves into the nucleus and regulates the expression of a host of target genes. Hundreds of p53-responsive genes have been reported, with diverse biological functions, but the key function of p53 is to act as a major barrier to tumorigenesis by responding to cell stress.
Cell stress causes aberrations, such as mutations, to be introduced into the cell's DNA that, if allowed to accumulate, can eventually lead to the development of cancer. Thus, an appropriate response to cell stress is essential to maintaining the integrity of the genome and preventing cancer. Under normal conditions, p53 is present at low levels in an inactive form, kept in check principally via a protein called murine double minute 2 (MDM2), which adds ubiquitin molecules to p53, "tagging" it for destruction by the cell's degradative machinery.
Under stress conditions, for example, if DNA is damaged, p53 is activated through posttranslational modification, such as phosphorylation, and accumulates in the nucleus in an active form. Activated p53 initiates numerous cell signaling pathways that ultimately drive 1 of 2 outcomes, depending on the type of cell and extent of the damage: (1) the cell cycle is halted, meaning the cell is unable to divide and form new cells until the damage has been repaired, preventing damaged DNA from being passed on to new cells; or (2) the cell is driven to commit suicide (apoptosis).When the Barrier Is Breached
The importance of p53 as a tumor suppressor is reflected in the fact that it is mutated in more than half of all human cancers. More than 18,000 mutations in the TP53 gene have been identified thus far. It is most commonly mutated in lung (70%), colon, head and neck, ovarian, bladder (60%), and stomach (45%) cancers. Approximately 90% of mutations are found within the DNA-binding domain, rendering p53 unable to activate target genes.
Germinal mutations in p53 are associated with the rare Li-Fraumeni syndrome, in which individuals are predisposed to a variety of cancers.
In addition to mutations in TP53, p53 function can also be disrupted through a number of other routes, including alterations in mediators of p53 function, such as MDM2, and viral inactivation of p53. In 90% of cervical cancers, p53 is inactivated by a human papillomavirus-encoded protein, E6.2 Sides to the p53 Coin
As the vital role of p53 was uncovered, the excitement reached a crescendo, and p53 became the focus of intensive cancer research around the globe. There was much speculation about the significant potential for p53-targeted cancer therapies, yet more than 30 years later that potential has yet to be realized.
Part of the complication arises from the finding that p53 has the potential to play 2 opposing roles in cancer progression: killer and protector. The foundation of conventional treatments, such as chemotherapy and radiation therapy, rests on the premise that they induce cellular damage, which stimulates p53-dependent apoptosis, killing off tumor cells. However, p53 may also inadvertently help tumor cells to survive by activating cellular senescence (permanent cell cycle arrest) pathways instead of apoptotic pathways.
It has been reported, for example, that some types of breast cancer with wild-type p53 show resistance to chemotherapeutic regimens, and a growing number of p53-induced survival genes have been identified. It is currently unclear how p53 determines whether to induce apoptosis or senescence, but this is an area of rapidly expanding research interest.
Not the Usual Suspects
Interest in p53 has driven original approaches to drug discovery that could have widespread applications. ”