Transcript 113867_Genetics_of_Cancer_2

Genetics of Cancer
Part 2
Review
• Two mutations must occur:
Review
• Two mutations must occur:
• Protooncogene stuck in the “on” position
(gas pedal down), constantly stimulating
cell division
Review
• Two mutations must occur:
• Protooncogene stuck in the “on” position
(gas pedal down), constantly stimulating
cell division
• Tumor Suppressor Gene inactivated
(brakes disconnected from accelerating
car)
What else must happen?
• External controls overcome
• Cells not limited by:
 Crowding
 Lack of attachment
 Lack of nutrients
What else must happen?
• Telomerase must be present to create
cellular immortality.
What else must happen?
• Telomerase must be present to create
cellular immortality.
• Most human cells divide 50-100 times
before entering G0 permanently or
committing cell suicide (apoptosis)
Telomerase
• OK, but…how does a cell know it has
divided 50-100 times???
Telomerase
• OK, but…how does a cell know it has
divided 50-100 times???
• Tips of chromosomes are capped with a
sequence of bases (TTAGGG) repeated
1000’s of times.
• Each division removes 50-200 of these
bases
Telomerase, con’t
• TTAGGGTTAGGGTTAGGGTTAGGG
TTAGGGTTAGGGTTAGGGTTAGGG
TTAGGGTTAGGGTTAGGGTTAGGG
TTAGGGTTAGGGTTAGGGTTAGGG
TTAGGGTTAGGGTTAGGGTTAGGG
TTAGGGTTAGGGTTAGGGTTAGGG
TTAGGGTTAGGGTTAGGGTTAGGG
TTAGGGTTAGGGTTAGGGTTAGGG
TTAGGGTTAGGGTTAGGGTTAGGG
Shortening…
• TTAGGGTTAGGGTTAGGGTTAGGG
TTAGGGTTAGGGTTAGGGTTAGGG
TTAGGGTTAGGGTTAGGGTTAGGG
TTAGGGTTAGGGTTAGGGTTAGGG
TTAGGGTTAGGGTTAGGGTTAGGG
TTAGGGTTAGGGTTAGGGTTAGGG
TTAGGGTTAGGGTTAGGGTTAGGG
Shortening, until…
• TTAGGGTTAGGGTTAGGGTTAGGG
TTAGGGTTAGGGTTAGGGTTAGGG
TTAGGGTTAGGGTTAGGGTTAGGG
TTAGGGTTAGGGTTAGGGTTAGGG
Shortening, until…
• TTAGGGTTAGGGTTAGGG
• It can’t divide any longer!
Stem Cells
• Stem cells produce cells (sex cells, blood,
hair) that need to be replaced regularly must keep dividing!
Stem Cells
• Stem cells produce cells (sex cells, blood, hair)
that need to be replaced regularly - must keep
dividing!
• Telomerase is an enzyme that rebuilds the
telomeres (adds TTAGGG)
• If telomeres don’t get shorter, cells don’t get
older
Back to cancer cells…
• Cancer cells have a mutation that allows
the production of telomerase.
• Leads to cells being immortal that should
die out.
• Telomerase = gas tank!
Metastasis must spread
cancerous cells
• Cells spread via the circulatory or
lymphatic system
• 99% of cancer cells die en route, but some
lodge in capillaries or lymph nodes
• Cancer cells can break down material
between cells to travel within tissues,
leading to new colonies
Cancer and inheritance
• Two-hit hypothesis: TSG’s are inherited in
pairs (as are all genes) and both copies
must be mutated since they function as
recessive alleles
Cancer and inheritance
• Inherited one mutant TSG? You’re prone
to developing cancer early in life (middle
age or earlier)
• Two good TSG’s? Cancer may come
later in life, if at all.
Cancer and inheritance
• Inheritance is only a small part of
developing cancer (15% of the risk of
colon cancer is due to inheritance, breast
cancer 7%)
• Environmental factors often more important
determinant
p53
• “THE GUARDIAN OF THE GENOME”
p53
• “THE GUARDIAN OF THE GENOME”
• Your primary TSG
• Mutated in 55% of all cancers
p53
• Activated when DNA damage is bad
• 1st - Halts cell cycle
p53
• Activated when DNA damage is bad
• 1st - Halts cell cycle
• 2nd - Starts DNA repair and restarts cell
cycle if successful
p53
• Activated when DNA damage is bad
• 1st - Halts cell cycle
• 2nd - Starts DNA repair and restarts cell
cycle if successful
• 3rd - Causes apoptosis (cell suicide) if
repair unsuccessful
Review
• Gas pedal =
Review
• Gas pedal = protooncogene
Review
• Gas pedal = protooncogene
• Brake =
Review
• Gas pedal = protooncogene
• Brake = tumor suppressor gene
Review
• Gas pedal = protooncogene
• Brake = tumor suppressor gene
• Gas tank =
Review
• Gas pedal = protooncogene
• Brake = tumor suppressor gene
• Gas tank = Telomerase (adds telomeres
TTAGGG)
Review
• Two-hit hypothesis?
Review
• Two-hit hypothesis = BOTH copies of a
TSG must be mutated
Review
• Two-hit hypothesis = BOTH copies of a
TSG must be mutated
• Guardian of the cell?
Review
• Two-hit hypothesis = BOTH copies of a
TSG must be mutated
• Guardian of the cell = p53
Review
• Two-hit hypothesis = BOTH copies of a
TSG must be mutated
• Guardian of the cell = p53
• Cell suicide?
Review
• Two-hit hypothesis = BOTH copies of a
TSG must be mutated
• Guardian of the cell = p53
• Cell suicide = apoptosis