p53 is a protein that promotes apoptosis (cell death) or senescence, which is a permanent stop in the cell cycle, characterized by specific changes in morphology and gene expression, which differentiates it from quiescence or reversible cell stop that acts as a tumor suppressor.
Detecting cellular stress and in response to signs of exaggerated proliferation, DNA damage, hypoxia, telomere shortening etc. induces the above
Its gene was initially described as an oncogene, it is related to different types of cancer, it has been called the guardian of the genome because it stops the cell cycle in case of mutation
The p53 gene (TP53) is a gene that is mutated in many cancers, and is the most common gene mutation found in cancer cells, about 50% have a p53 mutation).
When inactivated, it can also play a role in the persistence, growth, and spread of a developing cancer.
-Function of the p53 gene
There are two types of genes that are important in the development and growth of cancers: oncogenes and tumor suppressor genes.
Often, there is a buildup of mutations in both oncogenes and tumor suppressor genes, which is responsible for cancer development.
Eighty percent of the point mutations in p53 detected in human cancers are located in the DNA-binding domain of the protein.
In addition, p53 activates the transcription of the family of microRNAs, which prevent the translation of specifics, important for inducing a stop in the cell cycle and apoptosis, fundamental in the p53 response.
-Oncogenes and Tumour Suppressor Genes
Oncogenes arise when normal genes present in the body (proto-oncogenes) are mutated causing them to be activated. These genes encode proteins that control cell division.
Tumor suppressor genes, on the other hand, encode proteins that work to repair damaged DNA (so that a cell cannot become a tumor cell), or cause death, if that is not possible.
They are involved in the regulation of cell division or angiogenesis (the growth of new blood vessels to feed a tumor).
One type of tumor suppressor gene that most people are familiar with is the BRCA gene. Mutations in the BRCA gene are known to be associated with the development of breast cancer and other tumors.
The p53 gene is mutated in about 50% of cancer cells, but in addition to its role in tumor suppression, cancer cells themselves can find ways to inactivate and alter the gene that lead to new functions that help sustain the growth of a cancer.
This is known as gain of function. Some of these function gains may include
Resistance to anti-cancer drugs
Regulation of metabolism (to give cancer cells an advantage over normal cells)
Promote the spread of the tumor (metastasis)
Increase the growth of the tumor
Inhibit the apoptosis of cancer cells
Inducing genomic instability
Dodging the immunity
-p53 Genetic mutations
A mutation in the p53 gene (located on chromosome 17) is the most common mutation found in cancer cells . There are two primary types: germline and somatic.
-Germinal and somatic mutations
Germline mutations (hereditary mutations) are the type of mutations that produce a genetic predisposition to cancer.
Mutations are present from birth and affect every cell in the body. Genetic tests are now available to check for several germline mutations that increase the risk of cancer, such as mutated BRCA genes.
Germline mutations in the TP53 gene are rare, and are associated with a specific cancer syndrome known as the Li-Fraumeni syndrome that develop sarcomas or cancer as children or young adults.
The germline mutation is associated with a high lifetime risk for cancers such as breast, bone, muscle, and other cancers.
Somatic mutations (acquired mutations) are not present from birth, but arise in the process of a cell becoming a cancer cell.
They are only present in the type of cell associated with the cancer (such as lung cancer cells), and not in other cells of the body. Somatic or acquired mutations are by far the most common types of cancer-associated mutations.
How the p53 gene can be damaged by losing its function
The p53 gene can be damaged (mutated) by cancerous substances in the environment (carcinogens) such as tobacco smoke, ultraviolet light and others such as environmental pollutants.
-If gene p53 is deactivated:
If the gene is inactivated, it no longer codes for the proteins that lead to the functions mentioned above.
Thus, when there is DNA damage in another region of the genome, the damage is not repaired and may lead to the development of a cancer.
Mutations in the p53 gene have been one of the greatest challenges in cancer treatment, as these genes work to maintain the stability of the genome.
-Cancers associated with the p53 gene:
Some of them include:
Leukemias, lymphatics, Hodgkin’s disease
Breast cancer: The TP53 gene is mutated in about 20-40% of breast cancers.
Brain cancer (various types)
Squamous cell cancer of the head and neck
Lung cancer: The TP53 gene is mutated in most small cell lung cancers.
Osteosarcoma (bone cancer) and myosarcoma (muscle cancer)
Because of the great importance of TP53 mutations in cancer, ways are being sought to reactivate the gene.
Gene therapy with p53 continues to be in clinical trials
Most p53 mutations involve the substitution of an amino acid in the DNA-binding domain, with the consequent loss of its function as a transcription factor.
The goal of some anti-cancer treatments that target p53 is to restore the structure and function of the protein.
Some drugs of the thiosemicarbazone family, called zinc metalochaperones, allow the restoration of the primitive structure, correcting a defective bond with zinc, thus recovering normal folding and function.
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-Kumar, MBBS, MD, FRCPath, V.; Abul K. Abbas, MBBS, Nelson Fausto, MD and Jon Aster, MD (2009). «Molecular basis of cancer. In Saunders (Elsevier), ed.Robbins & Cotran Pathologic Basis of Disease.
-NIH U.S. National Library of Medicine: Genetics Home Reference [Internet]. Bethesda (MD): U.S. Department of Health and Human Services; What is a gene mutation and how do mutations occur?; 2018 Jun 26 [cited 2018 Jun 29]; [about 2 screens]. Available from:https://ghr.nlm.nih.gov/primer/mutationsanddisorders/genemutation