Lecture 3: Oncogenes and Tumor Suppressor Genes

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Lecture 3 Oncogenes and Tumor Suppressor Genes
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Peyton Rous 1879-1970 Nobel Prize for Medicine
1966
Rous Sarcoma Virus is a retrovirus, like HIV
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Reverse transcriptase
Envelope protein
Capsid protein
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Where did src come from? It certainly doesnt
appear to be part of the virus!!!
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Src is a proto-oncogene
I entered Gettysburg College intent on preparing
for medical school. But my ambition was far from
resolute. Every new subject that I encountered in
college proved a siren song. I imagined myself an
historian, a philosopher, a novelist, rarely a
scientist.
J. Michael Bishop, 54 Nobel Prize, 1989
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v-src and c-src
Exons have been removed from v-src
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How can a proto-oncogene become an oncogene?
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A translocation between chromosomes 9 and 22
responsible for chronic myelogenous leukemia. The
smaller of the two resulting abnormal chromosomes
is called the Philadelphia chromosome after the
city where the abnormality was first recorded
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abl is a tyrosine kinase proto-oncogene (Abelson
leukemia virus) bcr (breakpoint cluster region)
is expressed abundantly in hematopoietic tissue.
bcr expression drives abl expression and excess
cell division.
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Translocation associated with EBV viral infection
in West Africa
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Gene amplification. In this example the myc
proto-oncogene has been amplified. Chromosomes
are stained with a red fluorescent dye and the
multiple copies of the myc gene are detected by
in situ hybridization with a yellow fluorescent
probe.
myc tandem repeats
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Cancer-causing mutations are of two types.

• Dominant Oncogenes
• Accelerator. Acts positively to STIMULATE
  proliferation. One mutation will do. There are
  about 100 known oncogenes (ras, src, etc.)
• Recessive Tumor-Suppressor Genes
• Brake. Acts negatively to STOP proliferation.
  Both alleles must be knocked out for cancer.
• the retinoblastoma gene (Rb) and p53 are two of
  several tumor suppressor genes

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Child with hereditary retinoblastoma
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Rb suppresses tumor formation by blocking entry
of the cell into S phase. Block over-ridden by
cdk-cyclin
E2F transcription factor
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gt50 of all human cancers have two mutant p53
alleles
The G1/S checkpoint
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Guardian of the genome p53 protects human DNA
p53 is a sensor of DNA damage and a mobilizer of
emergency responses to genetic injury
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G1 checkpoint
Protein kinase
Ubiquitin ligase
DNA damage results in active P53, a transcription
factor that causes (1) Cdk-cyclin inhibition
stopping cell division (Entry into S with damaged
DNA would be a disaster!) and (2) programmed cell
death apoptosis.
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P53 -/- tumors are not sensitive to radiation
treatment or chemotherapy with DNA-damaging
drugs. Why?
Radiation and chemotherapy damage the DNA of
rapidly developing cells causing them to undergo
apoptosis.
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Family history of BRCA-1.
Responsible for 5 of all breast cancers
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Tumor Progession
Failure of G1/S checkpoint, damaged cells
proliferate and more mutations accumulate rapidly