The discovery that the v-src oncogene has a normal counterpart in the host cell was an important step toward determining the cellular genes that participate in cell growth and division. These normal cellular genes are called proto-oncogenes. They are involved in cell division, but do not themselves cause cancer. Only when they are mutated do they have the potential to cause cancer. Today, we know of scores of proto-oncogenes, most of which were identified through the study of cancer-causing viruses in chickens, mice, and cats.

Oncogenes also play a major role in human cancers. Most human cancers are not caused by viruses. Instead, human proto-oncogenes can be mutated into cancer-causing oncogenes by environmental agents such as chemical pollutants. For example, organic chemicals called aromatic amines present in cigarette smoke can enter cells and damage DNA, resulting in mutations that can convert a proto-oncogene into an oncogene.

What types of functions are performed by the products of proto-oncogenes? Nearly every protein that performs a key step in a signaling cascade that promotes cell division can be the product of a proto-oncogene. These include growth factors, cell-surface receptors, G proteins, and protein kinases. Each of these can be mutated to become oncogenes.

Let’s consider an example of a proto-oncogene. In Chapter 9, we discussed platelet-derived growth factor, or PDGF. This protein promotes cell division by binding to and dimerizing a receptor kinase in the membrane of the target cell. Dimerization of the receptor leads to the activation of several signaling pathways and the promotion of cell division. In one type of leukemia (a cancer of blood cells), a mutation in the gene that encodes the PDGF receptor results in an altered receptor that is missing the extracellular portion needed to bind the growth factor. The mutant receptor dimerizes on its own, independent of PDGF binding, and is therefore always turned on. The overactive PDGF receptor activates too many target proteins over too long a time period, leading to uncontrolled proliferation of blood cells.