Protooncogenes Oncogene pp' 62733

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Proto-oncogenes ? Oncogene pp. 627-33

• Proto-oncogene normal cell gene, involved in the
  contol of normal cell growth and proliferation
  (cell cycle control, transcription factor, DNA
  repair gene)
• oncogene mutated/de-regulated gene whose
  inappropriate expression leads to cancer

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shorter 22 philadelphia chromosome (Ph)
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9-22 reciprocal translocation occurs at a
specific place, leading to the formation of a
hybrid gene (bcr-abl)
Location of bcr gene
Location of c-abl gene
BCR-ABL Fusion Gene seen in gt90 of cases of
Chronic Myelogenous Leukemia
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Proto-oncogene gene product (e.g. abl gene
product is an enzyme) ? enzyme active site
Normal gene product can be regulated e.g enzyme
inhibited
Hybrid gene fusioncant be regulated e.g.
bcr-abl gene
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Proto-oncogene gene product (e.g. abl gene
product is an enzyme) ? enzyme active site
Normal gene product can be regulated e.g enzyme
inhibited
Hybrid gene fusioncant be regulated e.g.
bcr-abl gene
Drug designed to inhibit enzyme?
Gleevec...
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Deletions of normal cellular genes leading to
predispositions for cancer...
13q14 bilateral retinoblastoma

• individuals with deletion in this region are at
  increased risk for cancer of the retinas
• the loss of a gene in this region leaves only
  one functional copyits loss leads to cancer

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Initial deletion (first hit) increases likelihood
for cancer with loss of other allele...
Rb gene involved in cell cycle regulation (pp.
142-43 637-9)
Tumor suppressor gene
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Rb protein is important in cell cycle control
Cyclic inactivation of Rb protein will lead to
progression to S phase increase cell
proliferation.
Loss of Rb protein has same effect as
inactivationfrees EF2 and stimulates
proliferation...
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Reciprocal Translocations and Cancer Summary

• Breakpoints occur within genes (gene region
  copied into mRNA transcription unit)
• Rearrangement creates a hybrid gene
  (transcription unit)
• loss or gain of regulatory elements from one
  gene may now lead to inappropriate expression of
  the gene product (at RNA or protein level)
• cells carrying the mutation may now be at a
  proliferative advantage in a particular tissue
• eg. Chronic Myelogenous Leukemia Burkitts
  Lymphoma
• pp. 627-33 in Hartwell

Acentric and dicentric chromosomes
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Deficiencies and Cancer Summary

• tumor suppressor gene mutations... Loss of a
  gene critical for appropriate cell growth (e.g.
  cell cycle control, DNA repair) can cause
  predispositions to cancer in heterozygotes
• a second mutation arising in the non-deficiency
  chromosome leads to loss of suppressor gene
  product
• e.g. retinoblastoma and Rb Li Fraumeni syndrome
  and p53 gene BRCA1 and breast/ovarian cancer

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Paracentric Inversion (centromere not involved)
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Pericentric Inversion (centromere is involved)
(very unstable prone to loss)
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Crossovers in inversion heterozygotes generate
meiotic products with gene duplications and
deficiencies...
Crossovers within a paracentric inversion will
produce acentric and dicentric products that
contain duplications and deficiencies...
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Crossovers within a pericentric inversion will
produce meiotic products that contain gene
duplications and deficiencies, but also a
centromere...
Since crossover gametes are likely to be
inviable, inversions are used by geneticists to
suppress recombination between chromosomes in
genetic stocksthese balancer chromosomes
usually have multiple inversions
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Structural Chromosomal Polymorphisms
Population polymorphisms that do not lead to
clinical problems are often associated with
constitutive heterochromatin
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But position effects may influence expression
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Variegated Position Effects

• Variegated position effects can occur when a gene
  in a euchromatic region of the chromosome is
  transferred into or near a heterochromatic
  blocksee pp. 480-81

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(very unstable prone to loss)
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(very unstable prone to loss)
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Fragile X Syndrome

• Represent approximately 8 of males with mental
  retardation 1/1250 male births
• Other features include large testes, prominent
  jaw and head, large ears
• Detectable as a visible chromosomal abnormality
  on cell culture...

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When grown in a special medium, individuals with
a fragile X chromosome will show a narrowing or
gap called a fragile site...
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Typical Transmission Pattern for Fragile X
syndrome
??
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Trinucleotide Repeats within FMR-1 gene at
Fragile Site
Amplification of trinucleotide repeat occurs in
the germline of NTM daughters Abnormalities in
methylation pattern in area of repeats also
correlated with disease
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• approximately 15 of all pregnancies result in
  spontaneous abortions about 1/2 of these show
  chromosomal abnormalities
• In about 1/200 live births, a chromosomal
  abnormality can be detected, the majority being
  Down Syndrome and balanced translocations

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Prenatal Diagnosis

• Amniocentesis usually performed at 16 weeks of
  pregnancy, when fibroblasts can be safely
  collected from amniotic fluid. Requires
  mitogenic stimulation of cells prior to analysis
• Chorionic Villus Sampling (CVS) can be performed
  at the 9th week, from extra-embryonic cells that
  are actively dividing

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