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CANCER
Chapter 26 (3th edition)
Chapter 24 (3th edition)
JB Weitzmann and Nosh Yaniv
Nature 1999, 400 p401
DNA amplification:
Homogeneously Staining
Regions
FISH of
chromosome 4
HSR
DNA amplification:
double minute
chromosomes.
Rous sarcoma virus
Nobel Prize 1989
Chicken Rous Sarcoma Virus (RSV) carried an
oncogene called v-src and this gene was an intronless
version of a normal chicken gene called c-src.
DNA Damage
+
DNA Repair
Active
tumor suppressor
gene(s)
Proto-oncogene(s)
MUTATIONS
Inactive
tumor suppressor
gene(s)
Oncogene(s)
Gain-of-function
Dominant
phenotype
Loss-of-function
CANCER
Recessive
phenotype
Retinoblastoma.
EF2
Rb
Cdk2-cyclin E
P
+
DNA
mRNA
DNA polymerase
S-phase
Loss of heterozygosity
Loss of heterozygosity
Conditional mouse models.
Promotors regulated by tetracyclines:
transcription factors: transactivator (tTA) and reverse transactivator (rtTA).
Response Element: Tet(racycline) Operator (tetO)
v-SIS: retroviral oncogene coding for PDGF homolog.
Activation of the Epo receptor by erythropoietin or gp55 from Spleen focus-forming virus
(SFFV): erythroleukemia.
Papillomavirus E5 (44AA transmembrane protein) forms a complex with a endogenous
PDGF receptor protein thereby aggregating and activating two or more receptor
proteins.
EGF receptor oncogenes
(1) Overexpression of Her2
(human)
(2) Mutation of valine to
glutamine in transmembrane
domain: constitutively active
(mice)
(3) Loss of extracellular domain:
constitutively active (mice.
See also:
Overexpression of Her2
receptors in many human
breast cancers. The cells
respond and proliferate to
very small concentrations
of EGF.
Anti-Her2 mAb (Herceptin).
Domain structure of the normal Trk receptor and tropomyosin and the chimeric Trk
oncoprotein. (Neurotrophin protein tyrosine kinase receptor)
Tyrosine kinase.
The bcr-abl oncogene.
Philadelphia chromosome: Chronic myelogenous leukemia (Gleevec: STI571) and acute leukemia (in combination with a mutation in p53 or Rb).
c-fos (c-Jun) and c-myc are early response genes of many
growth factors.
p14ARF: a key activator of p53
p15
p14
p16
Risk of cancer increases:
1. p53 is defective.
2. MDM2 is over-active.
3. MDM2 is not enough sequestered
(inactive p14ARF)
What causes cancer?
1. Environmental carcinogens
- chemical (e.g., cigarette smoke)
- physical (e.g., UV radiation)
2. Host carcinogens (e.g., inflammation)
3. Viruses:
HTLV
Leukemia
TUMOR VIRUSES
Papiloma virus
Hepatitis B virus
Human Herpes virus 8 (Kaposi)
Human Herpes virus 4 (Epstein
Bar)
Human T lymphotropic virus
DNA viruses.
This woman has
hepatitis B and is
suffering from liver
cancer. She was a
Cambodian refugee
and died 4 months
after she arrived in
a refugee camp
(average life
expectancy after
diagnosis of liver
cancer is 6 months)
Kaposi syndrome: Human Herpes Virus 8)
Cutaneous B cell
lymphoma
Retroviruses
The formation of a
transducing retrovirus.
Base excision repair of a
mismatch.
Mismatch repair of
newly replicated DNA
Repair of double-strand breaks by
homologous recombination.
Error-prone repair
by end-joining.