The p53 protein is commonly called the "guardian of the genome" because of the key function it plays in protecting our DNA. A consequence of the abnormal function of the p53 protein in the cell, caused e.g. by genetic mutations, is the formation of various types of neoplasms. What other functions does the p53 protein play in the cell?

The p53 proteinalso known asTP53is the protein found in the cell nucleus of every cell. The p53 protein is commonly referred to as the "guardian of the genome" because it is essential in the regulation of DNA repair and cell division. The p53 protein was discovered in 1979 by Arnold Levine, William Old and David Lane. However, the first evidence of the existence of this protein suggested the results of experiments with the SV40 virus. SV40-infected mice had a dysregulated protein that gave rise to cancer cells. Later, this protein was finally identified as p53 and is now one of the most studied proteins in oncology. The p53 protein can exist in several isoforms in a cell. In total, about 12 human isoforms of p53 protein have been identified, e.g. p53α, p53β, p53γ, which differ in structure.

Protein p53 - what are its functions?

The p53 protein is made up of different fragments called domains. Each of the domains has strictly defined functions. The central part is the DNA-binding domain, which is responsible for the sequence-specific binding of the p53 protein.

It is very important because the p53 protein functions as the so-called a transcription factor that binds directly to DNA and controls the expression of key cell genes, e.g. related to DNA repair or programmed cell death. Other domains, such as TAD1 and TAD2, are located at the N-terminus of the p53 protein and are responsible for increasing or decreasing the expression of target genes.

In contrast, the domains at the C-terminus of p53 can interact with other cellular proteins, which in turn can regulate the activity of p53 itself. This structure of the p53 protein allows it to be the "guardian of the genome" and to control a number of molecular processes in the cell, such as:

  • activating repair systems when permanent damage occurs in DNA
  • inhibition of cell growth by keeping it at the G1 / S checkpoints during which damage recognition occurs. A cell stopped in this way has more time to repair DNA and only after repair will it continue its cyclemobile
  • initiation of programmed cell death, i.e. apoptosis, if the resulting DNA damage proves impossible to repair
  • maintaining normal cell aging processes, e.g. reacting to shortening telomeres
  • maintaining the proper condition of stem cells throughout a person's life

The p53 protein is classified as a tumor suppressor due to its anti-cancer functions, which means that it regulates cell division, stopping cancer cells from growing and dividing.

p53 protein - mechanism of action

When DNA in a cell is damaged by factors such as toxic substances and ultraviolet rays from sunlight, the p53 protein "decides" whether the DNA will be repaired or whether the damage is so severe that the entire cell should self-destruct.

If DNA can be repaired, the p53 protein activates DNA repair systems. Conversely, if DNA cannot be repaired, the p53 protein prevents further cell division and initiates apoptosis.

p53 protein - genetic mutations

In humans, the p53 protein is encoded by the TP53 gene on the short arm of chromosome 17. Hereditary or somatic (lifetime) mutations in the TP53 gene can cause loss of cell division control and an inability to induce apoptosis. As a result, DNA damage can accumulate in cells, which can lead to neoplastic transformation.

More than half of human cancers of various origins contain mutations in the TP53 gene. In turn, hereditary mutations predispose people to a neoplastic syndrome called Li-Fraumeni.

Most mutations in the gene encoding the p53 protein occur in the central part of the protein, which is the DNA-binding domain. These mutations primarily change single amino acids in the p53 protein that prevent it from binding to DNA.

The six most common TP53 mutations in cancer are R175, G245, R248, R249, R273 and R282. In addition to interfering with DNA binding, these mutations can give p53 new functions and, for example, increase tumor invasiveness and its ability to metastasize.

p53 protein - and cancer

Genetic analysis of many human cancers reveals the fundamental role of the p53 protein in suppressing cancer development. Somatic mutations in the TP53 gene have also been found in other types of cancer, such as:

  • lymphiaki
  • leukemias
  • colorectal cancer
  • bladder cancer
  • lung cancer
  • ovarian cancer
  • throat cancer
  • brain cancer
  • bone cancer
  • liver cancer

In somein cases, mutations in the gene encoding the p53 protein may indicate a worse prognosis of the tumor. For example, it has been shown that in breast cancer with a mutation in the TP53 gene, tumors tend to have a worse prognosis. This means that they are more aggressive, resistant to treatment with some anticancer drugs, and cause more frequent relapses.

In addition, somatic mutations in the TP53 gene are found in almost half of all lung cancers. Lung cancer can be broadly classified into two types: small cell lung cancer and non-small cell lung cancer, based on the size of the cells. Small cell lung cancers almost always carry mutations in the TP53 gene.

It is also worth knowing that some microorganisms, e.g. oncogenic viruses, can affect the functioning of the p53 protein. The E6 protein, encoded by the human papillomavirus (HPV), binds to and inactivates the p53 protein, leading to the formation of cervical cancer.

Read more: Papilloma can cause cancer. What is the human papillomavirus?

Protein p53 - Li-Fraumeni syndrome

Although somatic mutations in the TP53 gene occur in many types of cancer, Li-Fraumeni syndrome appears to be the only cancer syndrome associated with hereditary mutations in this gene.

Li-Fraumeni syndrome is a very rare disease in which inheriting only one non-functional copy of the gene encoding the p53 protein from your parents predisposes you to a number of cancers in early adulthood (including breast cancer).

At least 140 different mutations in the TP53 gene have been described in people with Li-Fraumeni syndrome.

  • Carcenogenesis, or cancer
  • What is a cancer mutation?
  • Cancer and genes. Hereditary neoplasms. Check if you are at risk

Category:

Oncology