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Many human genes produce proteins called tumor suppressors. Tumor suppressors inhibit transcription of genes that would cause increased replication. When a mutation occurs in any of these suppressors, replication and division become uncontrolled and tumors result. Table 14.3 lists some human tumor-suppressor genes.
A 53-kDa protein designated p53 has become the focus of feverish activ-ity in cancer research. Mutations in the gene that codes for p53 are found in more than half of all human cancers. When the gene is operating normally, it acts as a tumor suppressor; when it is mutated, it is involved in a wide variety of cancers. By the end of 1993, mutations in the p53 gene had been found in 51 types of human tumors. The role of p53 is to slow down cell division and to promote cell death (apoptosis) under certain circumstances, including when DNA is damaged or when cells are infected by viruses.
It is known that p53 binds to the basal transcription machinery (one of the TAFs bound to TFIID;). When cancer-causing mutations occur in p53, it can no longer bind to DNA in a normal fashion. The mode of action of p53 as a tumor suppressor is twofold. As shown in Figure 14.26, it is an acti-vator of RNA transcription; it “turns on” the transcription and translation of several genes. One of them, Pic1, encodes a 21-kDa protein, P21, that is a key regulator of DNA synthesis and thus of cell division. The P21 protein, which is present in normal cells but is missing from (or mutated in) cancer cells, binds to the enzymes known as cyclin-dependent protein kinases (CDKs), which, as their name implies, become active only when they associate with proteins called cyclins. Recall that cell division depends on the activity of cyclin-dependent kinases. Some of the oncogenes seen above work in such a way that the result is an overproduction of the CDK proteins, which keeps the cells dividing continuously. Normal levels of p53 protein cannot turn these genes off in cancer cells, but they could do this in normal cells. In normal cells, the result is that the cell cycle remains in the state between mitosis (in which cells divide) and the replication of DNA for the next cell division. DNA repair can take place at this stage. If the attempts at DNA repair fail, the p53 protein may trigger apoptosis, the programmed cell death characteristic of normal cells, but not of cancer cells.
The important point is that two different mechanisms are operating here. One is analogous to the brakes failing in your car (inadequate or defective p53 protein) and the other (overproduction of CDKs) is equivalent to the accelerator sticking in the open position—two opposite mechanisms with the same result: the car crashes.
A number of factors come together in explaining the variety of diseases we call cancer. Mutations of DNA lead to changes in the proteins that control cell growth, by either directly causing cell division or allowing it to occur by default. Still other mutations interfere with DNA repair. The possibility of finding new cancer therapies—and perhaps even cancer cures—is enhanced by under-standing these contributing factors and how they affect each other.
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