The p53 protein plays an integral role in the cell and is normally present in all cell types. The protein is localized in the nucleus where it functions as a transcription factor. The p53 protein is at the center of a large network of proteins that 'sense' the health of a cell and cellular DNA. The p53 protein is the conductor of a well orchestrated system of cellular damage detection and control. When damage is sensed, the activity of the p53 protein aids in the decision between repair and the induction of cell death (apoptosis).⁽¹⁾

As a transcription factor, p53 stimulates the transcription of a group of target genes. Among them, p21 is one of the most important. The product of the the p21 gene is a negative regulator of cyclin-dependent kinases, enzymes that are critical in the progression of the cell cyle and ultimately cell division.⁽²⁾ By stimulating the transcription of the p21 gene, p53 prevents cell proliferation. This stoppage gives the cell the opportunity to make repairs, if possible. If substantial DNA damage has occurred, the p53 protein can help to trigger cell death. The death of a cell that has incurred substantial DNA damage is beneficial to the organism because it prevents cells with deleterious mutations from proliferating.

As discussed in the introduction to this section, all cancer cells contain mutations in combinations of tumor suppressors and oncogenes. The removal of functional p53, the 'guardian of the genome,' from a cell allows for the accumulation of even more DNA damage and the division of cells that contain damaged DNA.

The mutation of the p53 gene is one of the most frequent genetic changes seen in cancer cells. In addition to mutations that arise during the growth and development of individuals (sporadic mutations), there are forms of cancer associated with the inheritance of a damaged version of p53. One such syndrome, the Li-Fraumeni cancer family syndrome, is associated with a wide variety of cancers.⁽³⁾ In addition, several viruses have evolved ways of inactivating the p53 protein including the human papillomavirus, the causative agent of cervical cancer.

Due to the central role played by this protein in the regulation of cell division, is a large amount of current research is committed to developing a safe method of restoring p53 gene function.

A Closer Look at Abnormal p53 and Cancer Development

A cell lacking functional p53 may or may not become cancerous, and correspondingly, a cell with normal p53 function may eventually lead to the formation of a cancerous growth. As discussed in the section on Mutation, to become cancerous, several different changes to the DNA of a cell must occur. One of the functions of p53 is to monitor the status of the cell's DNA. Along with a host of additional proteins, p53 helps to recognize and effect repairs to damaged DNA. The responses to damaged DNA include repair, cessation of cell division and cell death. Damage to the p53 gene does increase the likelihood of cancer development. Remember that since p53 is a tumor suppressor, both copies of the gene must be inactivated in order to see the full effects. There are several ways in which p53 can be inactivated:

Mutations
Alterations in the p53 gene have have several different effects on the activity of the gene, depending on the location of the alteration.

Mutations may occur in regulatory regions. These portions of the gene control how often, and when, the gene is transcribed (this region is called the promoter). A mutation in the promoter region can result in a decrease or absence of p53 in the cell.⁽⁴⁾
Mutations that occur in the protein coding region of the gene can impact the expression of the gene (or activity of the protein) in several ways:

A decrease in the activity of p53 as a transcription factor. The expression of the target genes of p53 that would be affected include p21 (a protein involved cell cycle regulation), Bax (a protein involved in the induction of apoptosis), and thrombospondin-1(an angiogenesis inhibitor).⁽⁵⁾⁽⁶⁾
A change in p53 that makes it more susceptible to degradation. If the p53 proteins in the cell are being degraded at a higher-than-normal rate they will not be able to perform their functions as tumor suppressors.⁽⁷⁾

Viral Inactivation
One of the functions of p53 is in 'guarding' the genome. Infection with viruses introduces foreign DNA into cells. p53, along with other proteins, is responsible for the cell's response to the presence of foreign DNA. Again, the responses include shutting down cell division and cell death. To avoid these responses, several different viruses have evolved ways of inactivating the p53 protein. An example of this is Simian Virus 40 (SV40) Upon infection with SV40, viral proteins are produced within the cell cytoplasm. One of the proteins produced is termed the Large T antigen. A function of this protein is the binding and inactivation the p53 protein. Other viruses such as Hepatitis and Human Papillomavirus produce similar proteins.

The elimination of functional p53 from the cell clears the way for cell division even in the presence of DNA damage. In the absence of p53, genetic instability as evidenced by increased muations and aneuploidy are likely to increase. The increase in genetic damage leads to the accumulation of defective tumor suppressors and oncogenes.⁽⁸⁾

Tumor Suppressors: p53 Function

A Closer Look at Abnormal p53 and Cancer Development