Download Lecture 7

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
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proto-oncogene= normal version of the gene
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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
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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
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Oncogenic retroviruses carry an extra gene
gag
pol
env
src (oncogene)
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The normal function of the src proto-oncogene encoded protein: it is a receptor
tyrosine kinase
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Receptor= molecule on cell surface that receives a signal from outside the
cell.
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Kinase= enzyme that adds phosphate groups to another molecule
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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
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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)
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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):
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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
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Example ras (Weinberg lab)
Gene
protein
GGC
aa1—aa2......aa12
Gly
GTC
Val
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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
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Can alter gene expression
Can make a version of the protein that induces cancer
Example: Translocation of c-myc in Burkitt’s lymphoma
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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)
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abl gene normally is on Chromosome 9
bcr gene normally is on Chromosome 22
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Translocation of abl gene to Chromosome 22 produces a fused gene
bcr-abl that produces an oncoprotein.
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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
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