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Pioneering studies by Peyton Rous beginning in 1911 led to the initial recognition that a virus could cause cancer when injected into a suitable host animal. Many years later, molecular biologists showed that his Rous sarcoma virus (RSV) is a retrovirus whose RNA genome is reverse-transcribed into DNA, which is then incorporated into the host-cell genome (see Figure 5-48). In addition to the “normal” genes present in all retroviruses, oncogenic transforming viruses such as RSV contain an oncogene: in the case of RSV, the v-src gene. Subsequent studies with mutant forms of RSV demonstrated that only the v-src gene, not the other viral genes, was required for cancer induction.

In the late 1970s, scientists were surprised to find that normal cells from chickens and other species contain a gene that is closely related to the RSV v-src gene. This normal cellular gene, a proto-oncogene, is commonly distinguished from the viral gene by the prefix “c” for “cellular” (c-SRC). RSV and other oncogenic transforming viruses are thought to have arisen by incorporating a normal host cellular proto-oncogene into their genome. Subsequent mutation in the incorporated gene then converted it into a dominantly acting oncogene able to transform host cells even in the presence of the normal c-SRC proto-oncogene. When this phenomenon was first discovered, it was startling to find that these dangerous viruses were turning the hosts’ own genes against them.

Because its genome carries the potent v-src oncogene, RSV induces tumors within days. RSV is said to be an acute retrovirus. In contrast, most oncogenic retroviruses induce cancer only after a period of months or years. The genomes of these slow-acting retroviruses, which are weakly oncogenic, differ from those of viruses such as RSV in one crucial respect: they lack an oncogene. All slow-acting, or “long-latency,” retroviruses appear to cause cancer by integrating into the host-cell DNA near a cellular proto-oncogene and activating its expression. The long terminal repeat (LTR) sequences in integrated retroviral DNA can act as enhancers or promoters for a nearby cellular gene, thereby stimulating its transcription. For example, in the cells from tumors caused by avian leukosis virus (ALV), the retroviral DNA is inserted near the MYC gene. These cells overproduce MYC protein; as noted earlier, overproduction of MYC causes abnormally rapid proliferation of cells. Slow-acting viruses act slowly for two reasons: integration near a cellular proto-oncogene (e.g., MYC) is a random, rare event, and additional mutations have to occur before a full-fledged tumor becomes evident.

In natural bird and mouse populations, slow-acting retroviruses are much more common than oncogenic retroviruses such as Rous sarcoma virus. Thus insertional proto-oncogene activation is probably the major mechanism by which retroviruses cause cancer. Although the only retrovirus known to cause human tumors is human T-cell lymphotrophic virus (HTLV), the huge investment made in studying retroviruses paid off both in the discovery of cellular oncogenes and in a sophisticated understanding of retroviruses, which later accelerated progress on the HIV virus that causes AIDS.

A few DNA viruses are also oncogenic. The normal replication cycle of these viruses does not involve integration into the host-cell genome, but viral DNA can become integrated into a chromosome of a host cell by cellular DNA repair processes. Although this is a rare event that is lethal to the virus, if the viral DNA expresses an oncogene, the host cell can become cancerous. For example, many warts and other benign tumors of epithelial cells are caused by the DNA-containing human papillomaviruses (HPV). A medically much more serious outcome of HPV infection is cervical cancer, the third most common type of cancer in women after lung and breast cancer. The Pap smear, which is used to sample the cervical tissue and screen for possible cancers, is thought to have reduced the death rate from cervical cancer by about 70 percent. We will learn more about HPV oncoproteins later in the chapter.

Unlike retroviral oncogenes, which are derived from normal cellular genes and have no function for the virus except to allow its proliferation in tumors, the known oncogenes of DNA viruses are integral parts of the viral genome and are required for viral replication. As we will see, the oncoproteins expressed from integrated viral DNA in infected cells act in various ways to stimulate cell growth and proliferation.