p53 is a tumor suppressor gene, and is one of the most widely-studied genes in the field of cancer. The gene encodes a protein which functions mainly as a transcription factor, i.e. it regulates the expression level of other genes. Normally, the level of p53 in the cell is very low; however, once the DNA in the cell nucleus is damaged (due to radiation, lack of oxygen, deprivation of nucleotides, etc.), p53 levels increase dramatically.
When the damage to the DNA is repairable, p53 activates genes which lead to cell division arrest and to the activation of DNA repair programs. Once the damage is repaired the cell can re-enter the division cycle. If the damage is too severe, p53 activates a different set of genes which lead to cellular aging and ultimately to apoptosis, programmed cell death.
For this significant regulatory role, p53 is often referred to as "guardian of the genome".
p53 and cancer
Malignant tumors are characterized by unchecked cell proliferation and by resistance to different stress conditions. Hence, a tumor cannot "afford" to express a functional p53 protein, which would impede its growth. For this reason, p53 is rendered inactive in about 50% of tumors, either by mutation or by deletion from the genome. Once p53 is mutated it cannot perform its original function (growth arrest and apoptosis), but instead it acquires new functions that actually help the tumor to grow.
Due to its high levels of expression, mutant p53 serves as a diagnostic and prognostic marker in various cancers, and current research is focused on developing drugs that elevate normal p53 levels in tumors, or alternatively modify the structure of the mutant protein in a manner that would restore its original functions.
Schematic representation of the p53 protein (left) interacting with a DNA molecule (adopted from Wikipedia).
Initially, p53 was believed to be an oncogene (a tumor promoting gene). It was only 10 years after its discovery that researchers realized that they were actually studying the mutant form of p53!
The prestigious Science journal named p53 "molecule of the year" in 1993.
Li-Fraumeni syndrome patients carry a mutation in one of their p53 alleles (one of the two copies of the gene). These patients develop cancer at a young age, and along their lifetime tumors can appear in different regions of their body.
Two professors from the Weizmann Institute, Moshe Oren and Varda Rotter, were among the first ones to study the p53 protein and they are still among the leaders of p53 research worldwide.
Department of Molecular Cell Biology
Weizmann Institute of Science
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