Two kinds of genes are changed in many cancers

The changes in the control of cell division that lie at the heart of cancer can be likened to the controls of an automobile. To make a car move, two things must happen: The gas pedal must be pressed, and the brake must be released. In the human genome, some genes act as oncogenes, which "press the gas pedal" to stimulate cell division, and some act as tumor suppressor genes, which "put the brake on" to inhibit it.

oncogenes. The first hint that oncogenes (from the Greek onco-, "mass") were necessary for cells to become cancerous came with the identification of virally induced cancers in animals. In many cases, these viruses bring a new gene into their host cells that stimulates cell division when it is expressed in the viral genome. But few types of human cancers are caused by viruses. It soon became apparent that the viral oncogenes had counterparts in the genomes of host cells that were not usually transcribed. So the search for genes that are damaged by carcinogens quickly zeroed in on these cellular oncogenes. Several dozen such genes were soon found.

Oncogenes are genes that have the capacity to stimulate cell division, but are normally "turned off" in differentiated,

Some oncogenes code for growth factors that stimulate cell division.

In cancer, mutations can cause overproduction of growth factors.

Some oncogenes code for growth factor receptors that stimulate cell division.

In cancer, a mutant receptor may no longer need growth-factor binding to stimulate cell division.

Some oncogenes code for transcription factors that can activate genes involved in cell division.

In cancer, mutant transcription factors always bind to their target gene promoter.

Some oncogenes code for growth factor receptors that stimulate cell division.

In cancer, a mutant receptor may no longer need growth-factor binding to stimulate cell division.

Some oncogenes code for transcription factors that can activate genes involved in cell division.

In cancer, mutant transcription factors always bind to their target gene promoter.

Some oncogenes code for proteins that participate in the transduction of signals for cell division.

In cancer, mutant proteins no longer need an external stimulus, and signal for constant cell division.

17.15 Oncogene Products Stimulate Cell Division Mutations can affect any of the several ways in which oncogenes normally stimulate cell division, thus causing cancer.

Some oncogenes code for proteins that participate in the transduction of signals for cell division.

In cancer, mutant proteins no longer need an external stimulus, and signal for constant cell division.

17.15 Oncogene Products Stimulate Cell Division Mutations can affect any of the several ways in which oncogenes normally stimulate cell division, thus causing cancer.

ffl Most people are born with two normal alleles for a tumor suppressor gene ffl Most people are born with two normal alleles for a tumor suppressor gene

Two Hit Hypothesis
17.16 The "Two-Hit"Hypothesis for Cancer (a) Although a single mutation can activate an oncogene, two mutations are needed to inactivate a tumor suppressor gene. (b) An inherited predisposition to cancer occurs in people born with one allele already mutated.

of a tumor suppressor gene requires that both alleles be turned off, which requires two mutational events. It takes a long time for both alleles in a single cell to mutate and cause sporadic cancer. But people with inherited cancer are born with one mutant allele for the tumor suppressor gene, and need just one more mutational event for its full inactivation (Figure 17.16).

The isolation of various tumor suppressor genes has confirmed Knudson's "two-hit" hypothesis. Some of these genes are involved in inherited forms of rare childhood cancers such as retinoblastoma (a tumor of the eye) and Wilms' tumor of the kidney as well as in inherited breast and prostate cancers.

An inherited form of breast cancer demonstrates the effect of tumor suppressor genes. The 9 percent of women who inherit one mutated allele of the gene BRCA1 have a 60 percent chance of having breast cancer by age 50 and an 82 percent chance of developing it by age 70. The comparable figures for women who inherit two normal alleles of the gene are 2 percent and 7 percent, respectively.

How do tumor suppressor genes act in the cell? Like the oncogenes, they are normally involved in vital cell functions (Figure 17.17). Some regulate progress through the cell cycle. The protein encoded by Rb, a gene that was first described for its contribution to retinoblastoma, is active during the G1 phase. In its active form, it encodes a protein that binds to and inactivates transcription factors that are necessary for progress to the S phase and the rest of the cell cycle. In non-

dividing cells, Rb remains active, preventing cell division until the proper growth factor signals are present. When the Rb protein is inactivated by mutation, the cell cycle moves forward independently of growth factors.

The protein product of another widespread tumor suppressor gene, p53, also stops the cell cycle at G1. It does this by acting as a transcription factor, stimulating the production of (among other things) a protein that blocks the interaction of a cyclin and a protein kinase needed for moving the cell cycle beyond G1. This gene is mutated in many types of cancers, including lung cancer and colon cancer.

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