Oncogenes
What causes cancer? Chemical factors (carcinogens) Physical factors (radiation, ionization) Biological factors (virus, bacteria, parasite) DNA Mutation or damage Oncogenes Tumor suppressor genes DNA repair genes Telomerase genes Increase stimulator signals Decrease inhibitory signals Increase DNA mutation in other genes Increase replication capacity Imbalance between cell growth, differentiation and death CANCER
gene A gene can be defined as a region of DNA that controls a hereditary characteristic It usually corresponds to a sequence used in the production of a specific protein or RNA
genes A gene carries biological information in a form that must be copied and transmitted from each cell to all its progeny This includes the entire functional unit: coding DNA sequences, non-coding regulatory DNA sequences
Oncogenes Oncogenes are mutated forms of genes that are normally present in a cell s These are genes whose action positively promotes cell proliferation The normal non-mutant versions are properly called proto-oncogenes
Oncogenes (1) viral oncogenes (2) cellular oncogenes From host genome (c-onc) or viruses (v-onc)
Proto-oncogenes segments of DNA, that are responsible for cell growth and proliferation. They normally remain dormant until activated during cell repliction Over 100 segments currently identified Cellular oncogenes, "c-onc" have 3 letter code Chromosomal location known for many human oncogenes Often produce a protein product - enzyme with regulatory activity Examples of proto-oncogenes include RAS, WNT, MYC, ERK and TRK
Oncogenes were first identified in cancer-causing retroviruses Francis Peyton Rous an American medical researcher, proved that viruses cause some types of cancer In 1910, Rous ground up a cancerous tumor from a chicken and filtered out everything larger than a virus
The resulting liquid produced cancer when injected into other chickens. For many years, scientists scoffed at Rous s discovery These scientists believed cancer could not be caused by a virus because the disease is not contagious In 1966, Rous shared the Nobel Prize for physiology or medicine for his work
J. Michael Bishop & Harold Varmus Bishop and Varmus found that a gene similar to the cancer-causing gene within the virus was also present in healthy cells In 1976 Bishop and Varmus, published their findings, concluding that the virus had taken up the gene responsible for the cancer from a normal cell After the virus had infected the cell and begun its usual process of replication, it incorporated the gene into its own genetic material Subsequent research showed that such genes can cause cancer in several ways. Even without viral involvement, these genes can be converted by certain chemical carcinogens into a form that allows uncontrolled cellular growth
Oncogenes play an important role in cancer development The protein kinase that causes Rous sarcoma formation is named Src Src is an oncogene (a cancer-causing gene found in viruses) Src is a mutant form of a gene normally found in host cells In the case of Src, the mutation results in an overactive protein kinase
DNA transfection assay is a new stragegy for detecting nonviral oncogens To verify this model, they asked question whether transformed cells carried mutated genes functions as oncogenes DNA from chemically transformed cells was introduced into normal cells by transfection and determine whether these recipient cells become transformed NIH3T3 cells: mouse fibroblasts in origin, contact-inhibited, nontumorigenic cell lines Transformation of NIH3T3 cells by gene transfer changes in cell morphology in culture, loss of contact inhibition, focal areas of dense layers termed foci Figure 4.2 The Biology of Cancer ( Garland Science 2007)
Genomic DNA from human tumors or tumor cell lines is transferred to NIH3T3 cells foci formation of morphologically altered cells that have tumorigenic properties Figure 4.2 The Biology of Cancer ( Garland Science 2007)
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16 What are the genes responsible for tumorigenic cell growth? Normal Proto-oncogenes Tumor suppressor genes + - Cell growth and proliferation Cancer Mutated or activated oncogenes Loss or mutation of Tumor suppressor genes ++ Malignant transformation
Reteroviral genome
Activation of oncogenese retrovirus 1. Acute transforming retrovirus rapidly produce tumors in newborn animals and carry genetic information capable of inducing tumors directly
2. The slowly transforming retroviruses do not carry oncogenes and induce tumors by integrating themselves adjacent to a cellular gene and altering its transcriptional regulation
Proto-oncogenes can be converted into oncogenes by.. 1) Recombination between retroviral DNA and a protooncogene 2) Deletion or point mutation in coding sequence 3) Chromosome rearrangement 4) Gene amplification/overexpression
Mechanisms for converting proto-oncogenes into oncogenes
Kleinsmith LJ. Principles of cancer biology. Pearson International Edition. Benjamin Cummings, San Francisco. 2006. p.160.
24 Amino acid substitutions in Ras family proteins (inactivates GTPase) amino acid position Ras gene 12 59 61 Tumor c-ras (H, K, N) Gly Ala Gln normal cells H-ras Gly Ala Leu lung carcinoma Val Ala Gln bladder carcinoma K-ras Cys Ala Gln lung carcinoma Arg Ala Gln lung carcinoma Val Ala Gln colon carcinoma N-ras Gly Ala Lys neuroblastoma Gly Ala Arg lung carcinoma Murine sarcoma virus H-ras Arg Thr Gln Harvey strain K-ras Ser Thr Gln Kirsten strain
Chromosomal translocation in Burkitt s lymphoma
Malarial parasites and EBV virus are an etiologiocal factor
27 CHROMOSOMAL REARRANGEMENTS OR TRANSLOCATIONS Neoplasm Translocation Proto-oncogene Burkitt lymphoma t(8;14) 80% of cases c-myc 1 t(8;22) 15% of cases t(2;8) 5% of cases Chronic myelogenous t(9;22) 90-95% of cases bcr-abl 2 leukemia Acute lymphocytic t(9;22) 10-15% of cases bcr-abl 2 Leukemia 1 c-myc is translocated to the IgG locus, which results in its activated expression 2 bcr-abl fusion protein is produced, which results in a constitutively active abl kinase
28 GENE AMPLIFICATION Oncogene Amplification Source of tumor c-myc ~20-fold leukemia and lung carcinoma N-myc 5-1,000-fold neuroblastoma retinoblastoma L-myc 10-20-fold small-cell lung cancer c-abl ~5-fold chronic myoloid leukemia c-myb 5-10-fold acute myeloid leukemia colon carcinoma c-erbb ~30-fold epidermoid carcinoma K-ras 4-20-fold colon carcinoma 30-60-fold adrenocortical carcinoma
Types of Oncogenes Four categories based on their gene products: growth factors or their receptors cytoplasmic protein kinases nuclear transcription factors (ex: c-myc) products that regulate apoptosis (block/induce)
Oncogenes product 1. Growth factor production: These growth factors activate signal transduction through different mechanisms Insulin like growth factor-2 Epidermal growth factor (EGF) activates the receptor bound tyrosine kinase
2. Growth factor receptors: Oncogene amplification my increase the number of normal growth factorreceptors on cell surface, hence increase signal transduction
3. GTP binding proteins: This is another form of disturbed signal transduction observed with mutation of the ras family of oncogenes
4. Tyrosin kinase activity: Oncogenes may code for the production of protein kinase enzymes which are involved in protein phosphorylation
5. DNA binding proteins: Some oncogene products (eg. Myc) are special phosphoproteins which specifically bind to DNA and interact with other genes which regulate mitosis
Kleinsmith LJ. Principles of cancer biology. Pearson International Edition. Benjamin Cummings, San Francisco. 2006. p.166.
Kleinsmith LJ. Principles of cancer biology. Pearson International Edition. Benjamin Cummings, San Francisco. 2006. p.166.
References Molecular Biology of Cancer, by F. Macdonald, C. H. J. Ford, Alan G. Casson, 2004. The Biology of Cancer, by Robert Allan Weinberg, 2007. Introduction to the Cellular and molecular biology of cancer, by Margaret A. Knowles, Peter Selby,2005. http://jkweb.mcb.berkeley.edu/external/research-inprogress/5-3/signaling/src_kinases.html http://nobelprize.org/nobel_prizes/medicine/laureates/19 66/ http://www.cancerquest.org/index.cfm?page=4982 http://www.bioinfo.org.cn/book/great%20experments/gr eat25.htm