What Are Proto-Oncogenes and How Do They Cause Cancer?

Proto-oncogenes are normal genes that provide instructions for proteins that regulate cell growth and division. This process is necessary for building tissues, repairing injuries, and maintaining daily bodily functions. In a healthy state, these genes are part of a complex network that ensures cells divide in an orderly and controlled manner.

Proto-Oncogenes: The Cell’s Growth Managers

Proto-oncogenes manage the cell’s life cycle by encoding proteins that stimulate cell division, also known as mitosis. They act like regulated gas pedals for cell growth, providing the push for cells to multiply when needed, such as during development or to replace damaged tissues. This function ensures that division is guided appropriately.

These genes also guide cell differentiation, the process where a cell becomes a more specialized type. By managing this, proto-oncogenes ensure new cells can perform specific jobs, such as becoming skin, liver, or nerve cells. This regulation helps maintain the function of tissues and organs.

The activity of proto-oncogenes is controlled by other genes and cellular signals. A cell receives cues that dictate when to grow and divide, and proto-oncogenes respond by producing proteins that start the cell cycle. This system ensures cell proliferation occurs only when and where it is needed.

The Switch: From Proto-Oncogene to Oncogene

A proto-oncogene becomes a cancer-promoting oncogene when its DNA sequence is altered. This activation frees the gene from its regulatory controls, leading to uncontrolled activity. One common mechanism is a point mutation, a small error in the DNA code, which can result in a protein that is permanently switched on and continuously tells the cell to grow.

Another activation method is gene amplification, where a cell produces multiple copies of a proto-oncogene. This leads to an excessive amount of the growth-stimulating protein, overwhelming the cell’s control systems. This is like having a gas pedal that is multiplied, leading to a rapid increase in cell division.

A third mechanism is chromosomal translocation, where a piece of one chromosome breaks off and attaches to another. If a proto-oncogene moves to a new location, it can fall under the control of a highly active promoter sequence. This new arrangement causes the gene to be expressed at much higher levels. Factors like chemical carcinogens, radiation, and certain viral infections can cause these genetic changes.

Oncogenes: Accelerators for Cancer Growth

Once activated, an oncogene drives cells to divide without stopping. The proteins produced by oncogenes can disrupt normal cell cycle checkpoints, which are safety mechanisms that ensure a cell is ready to divide. Bypassing these checkpoints permits continuous and unregulated cell division, a hallmark of cancer.

Oncogenes also help cells evade programmed cell death, a process called apoptosis, which the body uses to eliminate damaged or unneeded cells. By producing proteins that interfere with these death signals, oncogenes allow abnormal cells to survive and multiply instead of being destroyed.

The proteins from oncogenes can also encourage angiogenesis, the formation of new blood vessels. A growing tumor requires a blood supply for oxygen and nutrients, and oncogenes can signal surrounding tissue to create new vessels to feed it. This support system allows the tumor to expand and can facilitate its spread to other parts of the body, a process known as metastasis.

Common Proto-Oncogenes and Their Cancer Connections

The RAS gene family is one of the most frequently mutated proto-oncogenes in human cancers. Normally, RAS genes produce proteins that act as on/off switches in a signaling pathway controlling cell growth. Point mutations can cause the RAS protein to become permanently stuck in the “on” position, leading to constant signals for cell division. These mutations are common in pancreatic, lung, and colon cancers.

The HER2 gene, or ERBB2, is another well-known example. This proto-oncogene produces a protein receptor on the cell surface that receives growth signals. In some breast cancers, the HER2 gene is amplified, resulting in an excessive number of these receptors. This overabundance makes the cells overly sensitive to growth signals, driving tumor growth in what is known as HER2-positive breast cancer.

The MYC proto-oncogene provides instructions for a transcription factor, a protein that regulates other genes involved in cell proliferation. In some cancers, such as Burkitt’s lymphoma, a chromosomal translocation moves the MYC gene to a new location where it is continuously activated. This leads to the overproduction of the MYC protein, which then drives excessive cell growth.

Targeting Oncogenes: A Strategy in Cancer Therapy

The discovery of oncogenes has led to the development of targeted therapies for cancer treatment. These drugs are designed to interfere with the proteins produced by oncogenes, blocking their ability to drive cancer growth. By acting on specific molecular abnormalities in cancer cells, these treatments can be more precise than traditional chemotherapy.

One example is the use of tyrosine kinase inhibitors (TKIs), such as the drug imatinib. Imatinib targets the BCR-ABL fusion protein, an oncogene created by a chromosomal translocation found in chronic myeloid leukemia (CML). By blocking the activity of this oncogenic protein, imatinib can stop the proliferation of CML cells.

For HER2-positive breast cancer, monoclonal antibodies like trastuzumab (Herceptin) have been developed. These antibodies bind to the overexpressed HER2 receptors on cancer cells, which prevents them from receiving growth signals and marks them for destruction by the immune system. Such targeted approaches show how understanding specific oncogenes has led to more effective, personalized cancer treatments.