TP53 protein

ALSO KNOWN AS: Tumor protein 53, p53, cellular tumor antigen p53, tumor suppressor p53, phosphoprotein p53 (pp53), antigen NY-CO-13, guardian of the genome

DEFINITION: The TP53 protein is the product of the TP53 tumor-suppressor gene. As the molecular weight appears to be 53,000 when electrophoresed in a sodium dodecyl sulfate (SDS) polyacrylamide gel, it is referred to as TP53. The TP53 protein functions as a transcription factor that controls the activity of other genes. The TP53 gene is often referred to as the “guardian of the genome” because if the cell detects damage to its deoxyribonucleic acid (DNA), the TP53 protein prevents the replication of the damaged DNA, stimulates DNA repair, or stimulates cell death (apoptosis) so that damaged DNA is not passed to daughter cells. It also seems to be important in the process of suntanning.

Biological function: The TP53tumor-suppressor gene is located on chromosome 17 at 17p13.1 and is essential for cell function. The TP53 protein’s anticancer activity is exhibited by one of several mechanisms, many of which have not been clearly elucidated: activating mechanisms that repair DNA, arresting the cell cycle and preventing it from entering the DNA synthesis phase and passing damaged DNA on to daughter cells until damaged DNA can be repaired, and initiating apoptosis to prevent damaged DNA from being replicated and distributed to its daughter cells.

One well-characterized pathway involves the CDKN1A (p21) gene, so called because its product is a protein of 21,000 daltons. Normally, TP53 is sequestered in the nucleus by the protein HDM2. When bound to HDM2, TP53 is inactive and targeted for breakdown, keeping its cellular concentration low. If the cell detects damage to its DNA, oxidative stress, or membrane damage, TP53 becomes phosphorylated on its N-terminus by enzymes called kinases. These kinases include DNA-PK, CHK1, CHK2, ATM, ATR, CAK, and members of the MAPK (mitogen-activated protein kinase) family. When phosphorylated, TP53 dissociates from HDM2, becomes more stable, increases in concentration, changes its conformation, and becomes an active transcription factor that stimulates transcription of several genes, including the CDKN1A gene. The CDKN1A protein binds to and inactivates polypeptides that are required for the cell to enter the DNA synthesis phase of the cell cycle. Thus, the cell is prevented from replicating damaged DNA that could cause cancer and passing it on to its daughter cells.

The TP53 protein can also activate genes that stimulate apoptosis of cells with damaged DNA, activate genes necessary for repairing damaged DNA, and stimulate genes involved with the tanning reaction to protect cells from damaging ultraviolet (UV) light. By these and other mechanisms, TP53 prevents cell growth and even causes cell death to suppress cancer formation.

Structure of the protein: Active TP53 protein is a tetramer consisting of four identical polypeptides of 393 amino acids each. Many of the amino acid residues can be assigned to distinct functional domains. The 39 amino acid residues at the N-terminus are involved with HDM2 binding and activation of transcription of the CDKN1A gene. Residues 80 to 94 are responsible for TP53’s apoptosis activity, while amino acid residues 101 to 306 are responsible for TP53’s DNA-binding activity, an activity essential to its role as a transcription activator. The ability of TP53 monomers to polymerize into tetramers depends on amino acid residues 307 to 355. The C-terminus amino acids (356 to 393) are responsible for TP53’s localization in the nucleus and nonspecific binding to damaged DNA.

Cancer involvement: Mutations, usually simple amino acid replacement (missense) mutations, and deletions in the TP53 gene that alter the function of its product can severely limit its tumor-suppressor activity. People who inherit one defective TP53 gene are highly predisposed to developing Li-Fraumeni syndrome, which is characterized by cancer in a variety of tissues. More than 50 percent of all human cancers involve the TP53 gene, including between 40 and 60 percent of head and neck cancers, almost 50 percent of ovarian and lung cancers, 60 percent of colon cancers, between 50 and 70 percent of stomach cancers, and between 40 and 60 percent of bladder cancers.

Of the TP53 mutations that result in cancer, 90 percent affect the DNA-binding domain (amino acids 101 to 306). These mutations cause TP53 to be unable to bind to the CDKN1A gene and stimulate its expression.

Mutations in the TP53 gene affecting amino acid residues 307 to 355 are in the domain that allows TP53 to form tetramers with other TP53 molecules, a function necessary for its activity. TP53 molecules with one of these mutations form dimers with normal TP53 molecules, preventing their activity. Thus, these mutations are referred to as dominant loss-of-function mutations.

Medical researchers have developed treatment protocols that target TP53 mutations, more effectively treating possible cancers. Novel drug combinations, immunotherapies, and targeted therapies, in combination with chemotherapy and radiation, have improved the prognosis in patients diagnosed with cancer related to TP53 gene mutations. Plant substances and compounds such as curcumin are being investigated for their ability to be effective against mutations. Finally, advances in CRISPR/Cas9-mediated genome editing may be able to reverse mutations. 

Bibliography

Blanchet, Anais, et al. "Isoforms of the P53 Family and Gastric Cancer: A Ménage à Trois for an Unfinished Affair." Cancers, vol. 13, no. 4, 2021, doi.org/10.3390/cancers13040916. Accessed 3 July 2024.

Hainaut, Pierre, and Klas G. Wiman. Twenty-five Years of p53 Research. New York: Springer, 1999.

Herce, Henry D., et al. "Visualization and Targeted Disruption of Protein Interactions in Living Cells." Nature Communications, vol. 4, 2013, p. 2660.

Jaber, Nadia. “Lonsurf and Talzenna for Cancers with TP53 Mutations.” National Cancer Institute, 4 Apr. 2024, www.cancer.gov/news-events/cancer-currents-blog/2024/lonsurf-talzenna-cancer-tp53-mutations. Accessed 3 July 2024.

Kennedy, Margaret C., and Scott W. Lowe. "Mutant P53: It’s Not All One and the Same." Cell Death & Differentiation, vol. 29, no. 5, 2022, pp. 983-987, doi.org/10.1038/s41418-022-00989-y. Accessed 3 July 2024.

Malek, Sami. Advances in Chronic Lymphocytic Leukemia. New York: Springer, 2013.

Mukhopadhyay, Tapas, Steven A. Maxwell, and Jack A. Roth. p53 Suppressor Gene. New York: Springer, 1995.

“TP53 Gene.” MedlinePlus, 1 Feb. 2020, medlineplus.gov/genetics/gene/tp53. Accessed 29 June 2024.

“TP53 Genetic Test.” MedlinePlus, 6 Sept. 2023, medlineplus.gov/lab-tests/tp53-genetic-test. Accessed 3 July 2024.

Zambetti, Gerald, editor. Protein Reviews: The p53 Tumor Suppressor Pathway and Cancer. New York: Springer, 2005.