Oncogenes, Tumor Suppressor Genes, and Programmed Cell Death:- Oncogenes Are Mutant Forms of the Genes for Proteins That Regulate the Cell Cycle
Oncogenes were originally discovered in tumor-causing viruses, then later found to be closely similar to or de rived from genes in the animal host cells, protooncogenes, which encode growth-regulating proteins. During viral infections, the DNA sequence of a protooncogene is sometimes copied by the virus and incorporated into its genome (Fig. 12–47). At some point during the viral infection cycle, the gene can become defective by truncation or mutation. When this viral oncogene is expressed in its host cell during a subsequent infection, the abnormal protein product interferes with normal regulation of cell growth, sometimes resulting in a tumor. Proto-oncogenes can become oncogenes without a viral intermediary. Chromosomal rearrangements, chemical agents, and radiation are among the factors that can cause oncogenic mutations. The mutations that produce oncogenes are genetically dominant; if either of a pair of chromosomes contains a defective gene, that gene product sends the signal “divide” and a tumor will result. The oncogenic defect can be in any of the proteins involved in communicating the “divide” signal. We know of oncogenes that encode secreted proteins, growth fac tors, transmembrane proteins (receptors), cytoplasmic proteins (G proteins and protein kinases), and the nuclear transcription factors that control the expression of genes essential for cell division (Jun, Fos).
FIGURE 12–47 Conversion of a regulatory gene to a viral oncogene. 1 A normal cell is infected by a retrovirus (Chapter 26), which 2 inserts its own genome into the chromosome of the host cell, near the gene for a regulatory protein (the proto-oncogene). 3 Viral particles released from the infected cell sometimes “capture” a host gene, in this case a proto-oncogene. 4 During several cycles of infection, a mutation occurs in the viral proto-oncogene, converting it to an oncogene. 5 When the virus subsequently infects a cell, it introduces the oncogene into the cell’s DNA. Transcription of the oncogene leads to the production of a defective regulatory protein that continuously gives the signal for cell division, overriding normal regulatory mechanisms. Host cells infected with oncogene-carrying viruses undergo unregulated cell division—they form tumors. Proto-oncogenes can also undergo mutation to oncogenes without the intervention of a retrovirus, as described in the text.
Some oncogenes encode surface receptors with defective or missing signal-binding sites such that their intrinsic Tyr kinase activity is unregulated. For example, the protein ErbB is essentially identical to the normal receptor for epidermal growth factor, except that ErbB lacks the amino-terminal domain that normally binds EGF (Fig. 12–48) and as a result sends the “divide” signal whether EGF is present or not. Mutations in erbB2, the gene for a receptor Tyr kinase related to ErbB, are commonly associated with cancers of the glandular epithelium in breast, stomach, and ovary. Mutant forms of the G protein Ras are common in tumor cells. Theras oncogene encodes a protein with normal GTP binding but no GTPase activity. The mu tant Ras protein is therefore always in its activated (GTP-bound) form, regardless of the signals arriving through normal receptors. The result can be unregulated growth. Mutations in ras are associated with 30% to 50% of lung and colon carcinomas and more than 90% of pancreatic carcinomas.
