Classification of proto-oncogenes Growth factors e.g. V-sis (PDGF int-2(FGF a Receptor Tyrosine Kinases, e.g. Her-2/ neulerbbz EGFR a Membrane associated Non-Receptor Tyrosine Kinases, e.g. src Lck a Membrane associated G-Proteins e.g. Ras a Serine/Threonine Kinases e.g. Raf a Nuclear DNA-Binding/Transcription Factors, e.g. myc fos a Others o Apoptosis regulators, e.g. Bcl-2, o Regulators of cell cycle, e. g. Cyclin DI, CDK4
Growth factors, e.g. V-sis (PDGF), int-2 (FGF) Receptor Tyrosine Kinases, e.g. Her-2/ neu/ erbb2 (EGFR) Membrane Associated Non-Receptor Tyrosine Kinases, e.g. src, Lck Membrane Associated G-Proteins , e.g. Ras Serine/Threonine Kinases e.g. Raf Nuclear DNA-Binding/Transcription Factors, e.g. myc, fos Others Apoptosis regulators, e.g. Bcl-2, Regulators of cell cycle, e.g. Cyclin D1, CDK4 Classification of proto-oncogenes
Mechanisms of Oncogene Activation 1. Gene amplification, e.g. myc CCNDI 2. Point mutation, e.g. ras 3. Chromosomal rearrangement or translocation the transcriptional activation of proto-onc o the creation of fusion genes e.g. abl-bcr 4. Viral insertion activation e.g. C-Myc
Mechanisms of Oncogene Activation 1. Gene amplification, e.g. myc, CCND1 2. Point mutation, e.g. ras, 3. Chromosomal rearrangement or translocation the transcriptional activation of proto-onc. the creation of fusion genes, e.g. abl-bcr 4. Viral insertion activation, e.g. c-Myc
Excessive production of ormal prot DNA Point mutation Gene Normal amount of hyperactive protein Normal gene Excessive production of normal protein FIGURE 7-7 Overactivity of proto-oncogenes may be due to normal production of an abnormal protein(mutation in coding sequence) or excessive production of a normal protein (gene amplification or chromosome rearrangement)
Before translocation After translocation Derivative Chromosome 20 Chromosome 20 Duplicated area Derivative Chromosome 4 Translocation Chromosome Before duplication Amplification After duplication
Amplification Translocation
CHROMOSOMAL REARRANGEMENTS OR TRANSLOCATIONS Neoplasm Translocation Proto-oncogene Burkitt lymphoma t(8; 14)80%of cases C-myc t(8: 22)15% of cases t(2: 8) 5%of cases Chronic myelogenot t(9;22)90-95% of cases bcr-abl2 leukemia Acute lymphocytIc t(9;22)10-15% of cases bcr-abl2 Leukemia Ic-myc is translocated to the igG locus, which results in its activated expression 2bcr-abl fusion protein is produced, which results in a constitutively active abl kinase
CHROMOSOMAL REARRANGEMENTS OR TRANSLOCATIONS Neoplasm Translocation Proto-oncogene Burkitt lymphoma t(8;14) 80% of cases c-myc1 t(8;22) 15% of cases t(2;8) 5% of cases Chronic myelogenous t(9;22) 90-95% of cases bcr-abl2 leukemia Acute lymphocytic t(9;22) 10-15% of cases bcr-abl2 Leukemia 1c-myc is translocated to the IgG locus, which results in its activated expression 2bcr-abl fusion protein is produced, which results in a constitutively active abl kinase