So far, about 60 proto-oncogenes have been discovered (Tables 24-4 and 24-5 show a small

22 So far, about 60 proto-oncogenes have been discovered (Tables 24-4 and 24-5 show a small

selection); each of these can be converted into an oncogene that plays a dominant part in cancers of one sort or another. Most such genes have been encountered repeatedly, in a variety of mutant forms and in several kinds of cancer, suggesting that the majority of mammalian proto-oncogenes may already have been identified.

But what functions do these genes have in a normal healthy cell, that mutations in them should be so dangerous? Most proto-oncogenes code for components of the mechanisms that regulate the social behavior of cells in the body - in particular, the mechanisms by which signals from a cell's neighbors can impel it to divide, differentiate, or die. In fact, many of the components of cell- signaling pathways were first identified through searches for oncogenes, and a full list of proto- oncogene products includes examples of practically every type of molecule involved in cell signaling - secreted proteins, transmembrane receptors, GTP-binding proteins, protein kinases, But what functions do these genes have in a normal healthy cell, that mutations in them should be so dangerous? Most proto-oncogenes code for components of the mechanisms that regulate the social behavior of cells in the body - in particular, the mechanisms by which signals from a cell's neighbors can impel it to divide, differentiate, or die. In fact, many of the components of cell- signaling pathways were first identified through searches for oncogenes, and a full list of proto- oncogene products includes examples of practically every type of molecule involved in cell signaling - secreted proteins, transmembrane receptors, GTP-binding proteins, protein kinases,

The basic types of genetic accident that can convert a proto-oncogene into an oncogene are summarized in Figure 24-27. The gene may be altered by a point mutation, by a deletion, through

a chromosomal translocation, or by insertion of a mobile genetic element such as retroviral DNA. The change can occur in the protein-coding region so as to yield a hyperactive product, or it can occur in adjacent control regions so that the gene is simply overexpressed. Alternatively, the gene may be overexpressed because it has been amplified to a high copy number through errors in the process of chromosome replication. (The mechanism is discussed later - see Figure 24-34.) Specific types of abnormality are characteristic of particular genes and of the responses to particular carcinogens. For example, 90% of the skin tumors evoked in mice by the tumor initiator dimethylbenz[a]anthracene (DMBA) have an A-to-T alteration at exactly the same site in a mutant ras gene; presumably, of the mutations caused by DMBA, it is only the ones at this site that efficiently activate skin cells to form a tumor. Members of the myc gene family, on the other hand, are frequently overexpressed or amplified. The Myc protein normally acts in the nucleus as a signal for cell proliferation, as discussed in Chapter 17; excessive quantities of Myc cause the cell to embark on the cell-division cycle in circumstances where a normal cell would halt.

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