The TP53 gene provides instructions for making a protein called tumor protein p53. This protein acts as a tumor suppressor, a type of protein that regulates cell division. Because it plays a part in conserving the stability of a cell’s genetic information, or genome, it has been called the “guardian of the genome”.
The Normal Function of TP53
In its normal state, the p53 protein acts as a manager of cellular quality control, responding to various forms of cellular stress. When a cell’s DNA sustains damage from sources like ultraviolet radiation or chemical agents, the p53 protein detects this instability. This detection triggers a cascade of events designed to protect the organism from the proliferation of these damaged cells. The protein’s primary role is to act as a transcription factor, meaning it binds to DNA and regulates the expression of other genes.
One of the p53 protein’s main functions is to halt the cell cycle, a process known as cell cycle arrest. This pause provides the cell with a window of opportunity to repair the damage to its DNA. The p53 protein activates other genes that are responsible for carrying out these DNA repairs, ensuring the genetic code remains intact.
Should the DNA damage prove too extensive for repair, the p53 protein initiates a process called apoptosis, or programmed cell death. This is a self-destruct mechanism that eliminates the compromised cell, preventing it from passing on its damaged DNA to new cells. By triggering apoptosis, the p53 protein ensures that potentially cancerous cells are removed before they can form a tumor.
Role in Cancer Development
The protective functions of the p53 protein are compromised when the TP53 gene itself acquires mutations. These alterations, known as somatic mutations, are not inherited but occur during a person’s lifetime. Such mutations can prevent the production of a functional p53 protein or lead to the creation of an altered, ineffective version.
Without a functioning p53 protein, cells that have sustained DNA damage are no longer directed to pause for repair or to undergo apoptosis. These cells can then continue to divide, passing their genetic errors on to each subsequent generation of cells. This uncontrolled proliferation of damaged cells is a foundational aspect of cancer development.
The accumulation of further mutations in these dividing cells can lead to the development of a tumor. The absence of p53’s oversight allows for genomic instability, which is a characteristic of cancer cells. TP53 mutations are found in approximately 50% of all human cancers, making it the most commonly mutated gene in this context.
Inherited TP53 Mutations
While most TP53 mutations are acquired, it is possible for an individual to inherit a mutated copy of this gene from a parent. This type of mutation, called a germline mutation, is present in every cell of the body from birth.
The primary condition associated with inherited TP53 mutations is Li-Fraumeni syndrome. Individuals with this syndrome have a much higher lifetime risk of developing various types of cancer, including sarcomas, breast cancer, brain tumors, and leukemias. These cancers often appear at younger ages than they would in the general population.
Living with Li-Fraumeni syndrome means a life of heightened surveillance and preventative care. The presence of the germline TP53 mutation necessitates regular screenings and a greater awareness of cancer symptoms.
Therapeutic and Diagnostic Significance
The status of the TP53 gene in a tumor has become an important piece of information in the field of oncology. Doctors can test tumor cells to determine if a TP53 mutation is present. This information can help in predicting a patient’s prognosis, as tumors with TP53 mutations are often more aggressive and may be resistant to certain treatments.
Targeting TP53 directly for cancer therapy presents significant challenges. Because it is a tumor suppressor, the goal is often to restore its normal function, which is more complex than blocking the action of an overactive protein. One therapeutic strategy involves gene therapy, where a healthy copy of the TP53 gene is introduced into cancer cells.
Another area of research focuses on developing drugs that can reactivate the mutated p53 protein that is already present in the tumor cells. Some mutations cause the protein to misfold and lose its function; certain molecules are being investigated for their ability to help these proteins refold correctly and restore their tumor-suppressing activities.