Proto-Oncogenes and Tumor-Suppressor Genes
1. Two broad classes of genes
proto-oncogenes (e.g., ras) and tumor-suppressor genes (e.g., APC) play a key role in cancer induction. These genes encode many kinds of proteins that help control cell growth and proliferation; mutations in these genes can contribute to the development of cancer.2. Most cancers have inactivating mutations in one or more proteins that normally
function to restrict progression through the G1 stage of the cell cycle (e.g., Rb and
p16). Virtually all human tumors have inactivating mutations in proteins such as p53 that normally function at crucial cell-cycle checkpoints, stopping the cycle if a previous step has occurred incorrectly or if DNA has been damaged. Likewise, a constitutively active Ras is found in several human tumors of different origin. Thus normal growth control and malignancy are two faces of the same coin.
3. An oncogene is any gene that encodes a protein able to transform cells in culture or
to induce cancer in animals.
4. Of the many known oncogenes, all but a few are derived from normal cellular genes
(i.e., proto-oncogenes) whose products participate in cellular growth-controlling
pathways. For example, the ras gene is a proto-oncogene that encodes an intracellular signal-transduction protein;
5. Conversion, or activation, of a proto-oncogene into an oncogene generally involves a gain-of-function mutation.
6. Tumor-suppressor genes generally encode proteins that in one way or another inhibit cell proliferation. Loss of one or more of these “brakes” contributes to the development of many cancers.
7. Five broad classes of proteins are generally recognized as being encoded by tumor-suppressor genes:
• Intracellular proteins, such as the p16 cyclin-kinase inhibitor, that regulate orinhibit progression through a specific stage of the cell cycle
• Receptors for secreted hormones (e.g., tumor derived growth factor ?) that function to inhibit cell proliferation
• Checkpoint-control proteins that arrest the cell cycle if DNA is damaged or
chromosomes are abnormal
• Proteins that promote apoptosis and Enzymes that participate in DNA repair
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