Download Oncogene activation

Oncogenes
Human cell
Nucleus
Cytoplasm
Chromosomes
Once a Molecular Black Box
Today an Open Box
Growth
factors
Hormones
Cytoplasm
Nucleus
Oncogenic Viruses
Chicken sarcoma
Induced by Rous sarcoma virus
Peyton Rous (1879-1970)
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.
Nature, 260: 170-173 (1976)
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
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.
From L. J. Kleinsmith, Principles of
Cancer Biology. Copyright (c) 2006
Pearson Benjamin Cummings.
From L. J. Kleinsmith, Principles of
Cancer Biology. Copyright (c) 2006
Pearson Benjamin Cummings.
From L. J. Kleinsmith, Principles of Cancer Biology. Copyright (c) 2006 Pearson Benjamin Cummings.
From L. J. Kleinsmith, Principles of Cancer Biology. Copyright (c) 2006 Pearson Benjamin Cummings.
From L. J. Kleinsmith, Principles of Cancer Biology. Copyright (c) 2006 Pearson Benjamin Cummings.
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
C
T
G
Oncogenes
Normal cell
Cancer cell
Mutated/damaged oncogene
Normal
genes
regulate
cell growth
Oncogenes
accelerate
cell growth
and division
Proto-Oncogenes and Normal Cell Growth
Normal Growth-Control Pathway
Growth factor
Receptor
Signaling enzymes
Transcription
factors
Cell nucleus
DNA
Cell proliferation
Oncogenes are
Mutant Forms of Proto-Oncogenes
Inactive growth factor receptor
Inactive intracellular
signaling protein
Signaling protein from active oncogene
Activated gene
regulatory protein
Transcription
Cell proliferation driven by
internal oncogene signaling
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:
1979-1980 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:
1979-1980 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)
Human bladder cancer tissue
Figure 4.2 (part 1 of 2) The Biology of Cancer (© Garland Science 2007)
RAS (rat sarcoma), the first oncogene isolated from
human bladder cancer
Figure 4.10 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
Point mutation in Ras protooncogene
From L. J. Kleinsmith, Principles of Cancer Biology. Copyright (c) 2006 Pearson Benjamin Cummings.
From L. J. Kleinsmith, Principles of Cancer Biology. Copyright (c) 2006 Pearson Benjamin Cummings.
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)
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)
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.
From L. J. Kleinsmith, Principles of Cancer Biology. Copyright (c) 2006 Pearson Benjamin Cummings.
N-myc amplification and neuroblastoma
Figure 4.11b The Biology of Cancer (© Garland Science 2007)
Table 4.3 The Biology of Cancer (© Garland Science 2007)
erbB2/nue amplificated in about 25% of all breast and
ovarian cancers- ”herceptin” targeting ERBB2/HER2
Figure 4.6b The Biology of Cancer (© Garland Science 2007)
Chromosomal Translocation”Philadelphia Chromosome” containing
BCR-ABL fused oncogene
reciprocal exchange
From L. J. Kleinsmith, Principles of Cancer Biology. Copyright (c) 2006 Pearson Benjamin Cummings.
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)
DNA Rearrangements
From L. J. Kleinsmith, Principles of Cancer Biology. Copyright (c) 2006 Pearson Benjamin Cummings.
Oncogene activation
Insertional Mutagenesis
e.g., avian leukosis virus (ALV)
LTR (long terminal repeats) may stimulate the
transcription of proto-oncogene
See Fig. 7-11 top
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.
From L. J. Kleinsmith, Principles of Cancer Biology. Copyright (c) 2006 Pearson Benjamin Cummings.
Oncogene activation: Web