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Biology 207 Biology of Cancer Spring 2004 Lecture 7 “Oncogenes” Reading: Scientific American, “How Cancer Arises” Outline: 1. Cancer genes 2. Discovery of oncogenes 3. Nomenclature 4. Functions of proto-oncogenes Lecture: 1. Cancer Genes Oncogenes: Genes that promote cancer. Code for proteins that promote cell growth and division. Example: ras proto-oncogene= normal version of the gene oncogene=mutant or overexpressed form of gene Tumor suppressors: Genes that protect against cancer. Code for proteins that stop or regulate cell growth and division. Example: p53 How many genes are altered in cancer? Multistep model of carcinogenesis (Knudsen). Minimum of two genes altered. Human genome 3 billion base pairs of DNA 46 chromosomes (23 pairs) at least 40,000 genes ~80 oncogenes ~15 tumor suppressor genes 2. Discovery of oncogenes. Oncogenic viruses = viruses that cause cancer = tumor viruses How do viruses cause cancer? Rous sarcoma virus discovered in 1911 by Peyton Rous 1 A retrovirus, therefore has RNA as genetic material Infects chickens (most viruses are host specific) Causes sarcomas (muscle tumors) Why does it cause tumors? Carries the src oncogene Retroviruses contain similar genes for their core proteins (gag), reverse transcriptase (replication enzyme;pol) and envelope proteins (env). gag pol env _________________________________ Oncogenic retroviruses carry an extra gene gag pol env src (oncogene) ______________________________________________ The normal function of the src proto-oncogene encoded protein: it is a receptor tyrosine kinase Receptor= molecule on cell surface that receives a signal from outside the cell. Kinase= enzyme that adds phosphate groups to another molecule Tyrosine=an amino acid in proteins that phosphates can be attached to. The receptor tyrosine kinase normally helps cells respond to signals to grow and does not respond when there are no signals present. In the Rous sarcoma virus, The src oncoprotein is overexpressed (too much is made). Infected cells can receive and transmit more signals to the cell to grow and divide than are needed. Overgrowth of cells leads to cancer. 3. Nomenclature Many different oncogenes have been discovered (>80 so far). Oncogenes have three letter names, usually lower case and italicized. The naming conventions are rather confusing. Some examples: A. name may refer to the type of cancer src = sarcoma (cancer of muscle, bone, or connective tissue) 2 B. name may refer to scientist who discovered it abl = Abelson leukemia (scientist’s name, type of cancer) C. name may refer to species of animal the virus infects sis = simian (monkey) sarcoma The viral and cellular forms of oncogenes are often distinguished by prefixes v-src (viral form) c-src (cellular form) Common oncogenes implicated in mouse and human tumors oncogene ras associated cancers colon, lung, bladder (15-20% of all cancers) B-cell lymphomas c-myc Strategy for isolating the first cellular oncogene (ras): Race between two major labs: Weinberg versus Wigler Shih and Weinberg used the chemical carcinogen benzopyrene to create human tumor cell lines. Human tumor cell DNA and mouse cell lines were used in gene transfer expermiments. Presence of oncogene gives dominant phenotype of “transformation” (very cancer-like). Required recombinant DNA methods to “clone” the oncogene. Research was done especially carefully as a “double blind test”, so experimenter would not introduce bias into the results. Controls had to be done to make sure that a cellular gene and not a viral gene was isolated. At this time, the only oncogenes known were from viruses. When the isolated ras oncogene sequence and the normal ras protooncogene sequence were compared a single base pair change was found in the DNA that altered the ras protein. 4. Ways proto-oncogenes become oncogenes: A. point mutation in proto-oncogene 3 Example ras (Weinberg lab) Gene protein GGC aa1—aa2......aa12 Gly GTC Val normal ras proto-oncogene ras oncogene Change in DNA sequence (mutation) results in a change in the amino acid sequence of the protein. The protein normally is involved in cell signalling. Cancer turns the molecular switch into the “always on” position. B. Chromosome rearrangement Can alter gene expression Can make a version of the protein that induces cancer Example: Translocation of c-myc in Burkitt’s lymphoma Moves from Chromosome 8 to Chromosome 2, 14 or 22. Results in overexpression of normal protein Example: Rearrangement of abl and bcr genes in Chronic Myelogenous Leukemia (CML) abl gene normally is on Chromosome 9 bcr gene normally is on Chromosome 22 Translocation of abl gene to Chromosome 22 produces a fused gene bcr-abl that produces an oncoprotein. This translocation can be readily seen by examining the chromosomes. Rearranged chromosome 22 = “Philadelphia chromosome” Diagnostic for CML. C. Gene amplification Region of the genome is copied many times. More copies of the RNA and proteins can be made. Example: myc genes 4