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.