Oncogenes Human cell ChromosomesCytoplasm Nucleus

Once a Molecular Black Box

Today an Open Box CytoplasmNucleus Growth factors Hormones

Oncogenic Viruses Chicken sarcoma Induced by Rous sarcoma virus Peyton Rous ( ) Nobel Laurate of 1966 (shared w/ Charles Huggins)

Figure 3.2 The Biology of Cancer (© Garland Science 2007)

Figure 3.4a The Biology of Cancer (© Garland Science 2007)

Figure 3.7a The Biology of Cancer (© Garland Science 2007)

Figure 3.19 The Biology of Cancer (© Garland Science 2007)

From L. J. Kleinsmith, Principles of Cancer Biology. Copyright (c) 2006 Pearson Benjamin Cummings.

Discovery of Rous sarcoma virus (RSV) - Isolated from Chicken sarcoma - “src” required for oncogenicity - presence of src-like DNA sequences in normal cells: c-src as a cellular counter part - Ubiquitous distribution of c-src, not only in avian species but also mammalian species & evolutionarily conserved v-src descends directly from a c-src antecedent.

DNA related to the transforming gene(s) of avian sarcoma viruses is present in normal avian DNA Stehelin, D, Varmus, HE, Bishop, JM and Vogt, PK Nature, 260: (1976)

Genetic Theft Src might originally have been a cellular gene that was kidnapped by an ancestor of RSV, incorporated by RSV into its own genome, and then expoloited by the virus to transform normal cells into cancer cells– “Jekyll-to-Hyde” conversion

Figure 3.22 The Biology of Cancer (© Garland Science 2007)

From L. J. Kleinsmith, Principles of Cancer Biology. Copyright (c) 2006 Pearson Benjamin Cummings.

DNA Molecules The Building Blocks of the Genome DNA molecule (chromosome) Chemical bases A T C G

Oncogenes Mutated/damaged oncogene Oncogenes accelerate cell growth and division Cancer cell Normal cell Normal genes regulate cell growth

Proto-Oncogenes and Normal Cell Growth Receptor Normal Growth-Control Pathway DNA Cell proliferation Cell nucleus Transcription factors Signaling enzymes Growth factor

Oncogenes are Mutant Forms of Proto-Oncogenes Cell proliferation driven by internal oncogene signaling Transcription Activated gene regulatory protein Inactive intracellular signaling protein Signaling protein from active oncogene Inactive growth factor receptor

ONCOGENES Retroviral Oncogenes: 1) RSV 2) Source of the oncogene(src)? Identification of Oncogeses via transfection: 1944-Oswid Avery, Colin Madeal,Maclyn McCarth: --transfected active DNA to bactera 1971-Miroslay Hill and Janna Hillova -transfected DNA from RSV transformed cells to chick emmbroyo fibroblasts. ----src gene is sufficient to induce cell transformation

ONCOGENES Identification of Oncogeses via transfection: Robert Weinberg: --transfected DNA from chemically transformed cells or normal Cells to NIH 3T3 cells. --chemically transformed cells contained activated oncogene --normal cell contained proto-onocogene

ONCOGENES Identification of Oncogeses via transfection: Robert Weinberg: --transfected DNA from chemically transformed cells or normal Cells to NIH 3T3 cells. --chemically transformed cells contained activated oncogene --normal cell contained proto-onocogene

Figure 4.2 (part 2 of 2) The Biology of Cancer (© Garland Science 2007)

Figure 4.2 (part 1 of 2) The Biology of Cancer (© Garland Science 2007) Human bladder cancer tissue

Figure 4.10 The Biology of Cancer (© Garland Science 2007) RAS (rat sarcoma), the first oncogene isolated from human bladder cancer

“Enemies within” How are protooncogens activated? 1) Point mutation 2) Gene amplification 3) Chromosomal translocation 4) DNA rearrangement 5) Insertional mutagenesis

From L. J. Kleinsmith, Principles of Cancer Biology. Copyright (c) 2006 Pearson Benjamin Cummings. Point mutation in Ras protooncogene

From L. J. Kleinsmith, Principles of Cancer Biology. Copyright (c) 2006 Pearson Benjamin Cummings.

Figure 5.30 The Biology of Cancer (© Garland Science 2007)

Figure 5.31 The Biology of Cancer (© Garland Science 2007)

“Enemies within” How are protooncogens activated? 1) Point mutation 2) Gene amplification 3) Chromosomal translocation 4) DNA rearrangement 5) Insertional mutagenesis

Table 4.2 The Biology of Cancer (© Garland Science 2007)

From L. J. Kleinsmith, Principles of Cancer Biology. Copyright (c) 2006 Pearson Benjamin Cummings. Gene Amplification  abnormal appearance of chromosome regions  (e.g., homogeneously staining regions (HSRs)  and double minutes (DMs)

From L. J. Kleinsmith, Principles of Cancer Biology. Copyright (c) 2006 Pearson Benjamin Cummings.

Figure 4.11b The Biology of Cancer (© Garland Science 2007) N-myc amplification and neuroblastoma

Table 4.3 The Biology of Cancer (© Garland Science 2007)

Figure 4.6b The Biology of Cancer (© Garland Science 2007) erbB2/nue amplificated in about 25% of all breast and ovarian cancers- ” herceptin ” targeting ERBB2/HER2

From L. J. Kleinsmith, Principles of Cancer Biology. Copyright (c) 2006 Pearson Benjamin Cummings. Chromosomal Translocation- ”Philadelphia Chromosome” containing BCR-ABL fused oncogene reciprocal exchange

Figure 4.15a The Biology of Cancer (© Garland Science 2007)

Figure 4.12 The Biology of Cancer (© Garland Science 2007)

Figure 4.13a The Biology of Cancer (© Garland Science 2007)

Figure 4.13b The Biology of Cancer (© Garland Science 2007)

From L. J. Kleinsmith, Principles of Cancer Biology. Copyright (c) 2006 Pearson Benjamin Cummings. DNA Rearrangements

Oncogene activation

Insertional Mutagenesis See Fig top e.g., avian leukosis virus ( ALV ) LTR (long terminal repeats) may stimulate the transcription of proto-oncogene

From L. J. Kleinsmith, Principles of Cancer Biology. Copyright (c) 2006 Pearson Benjamin Cummings.

Figure 4.14 The Biology of Cancer (© Garland Science 2007)

From L. J. Kleinsmith, Principles of Cancer Biology. Copyright (c) 2006 Pearson Benjamin Cummings.

Oncogene activation: Web