big lessons from little worms
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Big lessons from little worms. Apoptosis. worm Image from Mingxue Cui. The worms are transparent. Worms are transparent.TRANSCRIPT
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Big lessons from little worms
Apoptosis
worm Image from Mingxue Cui
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The worms are transparent
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Worms are transparent <1000 cells
One can follow the individual lineage of each of the cells
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Deciphering the cell lineage of C. elegans
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Deciphering the cell lineage of C. elegans
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Cell death is also a “cell fate”
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Programmed cell death
Specific cells are dying in a programmed manner
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Programmed cell death (PCD)The mechanism: apoptosis
Also associated with the fight of our body against cancer tumors
Is this an active process?
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We know there is apoptosis
We know it is important in development and possibly in cancer
We don’t know whether it is an active processWe don’t know of any genes involved
Let alone, a pathway (if exists)
What do we do?
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Mutagenesis
Forward Genetics: random mutations
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They found the guy who gets rid of the body
Next, they found the murderer
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ced-1ced-3
ced-3 acts to promote cell death
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Is it murder or suicide?
ced-1ced-3
Mutant analysisThe gene is mapped and sequenced
Next step: does it have human homologes or is this just a worm-specific pathway?
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Is it a worm-specific gene or do we have human homologs?
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Apoptosis is carried out by proteins. It is an active process, not a passive death
- The ced-3 gene encodes a protease, conserved in evolution
- It kills cells by degrading their proteins
Now we also know that human caspase is involved in apoptosis
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A new mutation was isolated: ced-9
ced-9(-): ectopic cell death (cells that normally live, undergo apoptosis)
ced-1ced-3
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More and more mutants are isolated
Epistasis analysis and biochemical studies allow the scientists to build a pathway
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Genetic control of programmed cell death
CED-4No death signal
CED-4 is inactive
Death signal
CED-9
Activates CED-3 caspase for the killing
CED-9CED-4
ced-9 Cell deathced-3ced-4
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Gain of function mutations in bcl-2 were associated with human cancers (bcl= b cell
lymphoma resulting from a translocation event)
Our body uses the same apoptotic mechanisms used in PCD, for killing “bad” cells
Identify mutants in worms (with the simplest assay) and find human homologs
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Bob Horvitz
Lineage and programmed
cell deathBob Horvitz John Sulston Sydney Brenner
Physiology and Medicine 2002
Nobel Prize
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- Pro-apoptotic signals open up the channels, allowing cyt C to be released to the cytoplasm
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A simplified representation of apoptosis
NoxaProapoptotic(BH3-only)
Proapoptotic(multidomain)
Bax
Bcl-2
Cytochrome C
Apaf
Procaspase
Caspase
Mitochondria
All the regulators are from the same protein family (containing BH domains)
Antiapoptotic