CANCER
Chapter 26 (3th edition)
Chapter 24 (3th edition)
JB Weitzmann and Nosh YanivNature 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.
Proto-oncogene(s)
Oncogene(s)
Activetumor suppressor
gene(s)
Inactivetumor suppressor
gene(s)
CANCER
MUTATIONS
Gain-of-function
Loss-of-functionDominant phenotype
Recessive phenotype
DNA Damage+
DNA Repair
+
Rb EF2
Cdk2-cyclin E
P
DNA
mRNA
DNA polymerase
S-phase
Retinoblastoma.
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)
The bcr-abl oncogene.
Philadelphia chromosome: Chronic myelogenous leukemia (Gleevec: STI-571) and acute leukemia (in combination with a mutation in p53 or Rb).
Tyrosine kinase.
c-fos (c-Jun) and c-myc are early response genes of many growth factors.
p15 p16p14
p14ARF: a key activator of p53
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.
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