Apoptosis: Programmed Cell Death ???? A story about 7th October 2002

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ApoptosisProgrammed Cell Death????A story
about 7th October 2002

• ?3?
• ?????,??King,??,??,???,??,??

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Sydney Brenner

• 1927??(80?)
• ???
• ?????????
• established C. elegans as a novel experimental
  model organism

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John Sulston

• 1947??(60?)
• ???
• ??????
• mapped a cell lineage where every cell division
  and differentiation could be followed in the
  development of a tissue in C. elegans

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Robert Horvitz

• 1942??(65?)
• ???
• The Wellcome Trust Sanger Institute
• has discovered and characterized key genes
  controlling cell death in C. elegans

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• ???,???????
• Ex????????????

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• ??????????????
• ???????????????????

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??

• ??,??,??????????

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Apoptosis vs. PCD

• ???PCD??????????????
• ???????
• ????? vs.?????

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Apoptosis vs. Necrosis

• Apoptosis programmed cell death
• Necrosis un-programmed cell death

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Necrosis

• ??
• ???????CCl4??????
• ??
• ??
• ????????????
• ????????

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Apoptosis

• 1972 Kerr ??????

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Apoptosis vs. Necrosis
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Back to apoptosis

• ??,????????,??????(??????)
• ??,????????,??????(??????)

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Please refer to page 428 of your textbook
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2 main integration pathways

• Death receptor pathway
• Mitochondrial pathway
• Both pathways converge to a common execution phase

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Execution phase
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Multiples of 180200 bp fragments
Ladder
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Apoptosis in detail

• Signal
• Cell shrinkage/ Loss of cell-cell contact
• Condensation of nuclear chromatin
• Nuclear fragmentation
• Membrane ruffling/ blebbing
• Phagocytosis of apoptotic bodies

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E.g. FasL/TNF
Death factors
Bind to death receptorscluster and trimerise
E.g. Fas/TNFR
Recruits FADD
DED
Recruits pro-caspase 8 induced proximity
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???? ??????????? ?????PT
pore ( PT ??)
PT pore?????????????????
?????????????
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PT pore
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• PT pore ???
• 1. PT pore ????????????????
• (ANT???????????,????????????)
• PT pore ????????????
• (PT???????m????????????PT)
• PT pore ????????????
• (??????ATP?ADP?NAD???m )

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PT pore ??????
?PT pore ?cyclosporin A ?SH ?bongkrekacid ???,PT
pore ????
?PT pore??? ?????????????AIF
??????????C?
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• ??
• ????PT????????????
• ?????????
• ????????(?????bcl-2??or?????Bax??)???????????
• ???bcl-2?????m??? ??,???Bax?????m????

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???????

• ???ced9
• ????????? bcl-2(?ced9?????)

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??????

• P35??Caspases????,????P35? Caspase?????,??????
  ???????????????Caspases??
• CrmA????????,??????????????,???????????????P35?Cr
  mA??????

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??????

• FLIPs???Fas/TNFR1??????????DED???,?FADD?Caspase-
  8,10??,???????????,????Caspase8,10????????????????
  ??

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bcl-2??

• ???????,?????????
• ?????????ced-9?
• ???????????????????,???????????c?????????
• ???1-4?Bcl-2?????

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Apoptosis is all around us
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Where can we see apop.?

• Surprisingly..
• all multi-cellular organisms!
• And even some single.. _at__at_
• Team strategy.

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Lets see

• Animals!

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Apoptosis Inducer

• infected with a virus
• undergoing stress conditions (such as starvation)
• ionizing radiation
• toxic chemicals

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Apoptosis Function

• Reduce energy lost
• Prevent cancer development
• PCD
• Homeostasis

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In plants as well

• ??????

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In plants as well (2)

• Transduction ducts (?? ???)

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In plants (3)

• ???
• (?? ? ?)

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Afterthoughts

• Death is so useful
• What is life??

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ParadoxLife is dependent on cell death
Demonstration of single HT-29/B6 apoptotic cells.
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Inhibition of apoptosis Cancer

• Deletion/mutation of p53
• express high levels of Bcl-2
• FAS signaling

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• Cancers associated with viruses
• ex HPV (cervical cancer )
• EBV (lymphomas)
• Other cancer cells
• ex B-cell leukemias
• Melanoma
• FasL
• ex lung and colon cancer cells

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Excessive apoptosis Alzheimer

• Loss of neural cells
• Induced by beta-amyloid peptides
• (Abeta)

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• Abeta trigger toxicity via activation of caspases
• The activation of caspase-8 and 9 by Abeta and
  C31
• APP
• (1)a source of cytotoxic Abeta
• (2)represent a source of C31 contributing
  cytotoxic activity of Abeta

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Inappropriate apoptosis HIV

• Death of CD4 T cells most by apoptosis
• Expression of Nef gene in effected CD4 T cells

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????!

• Death is only the beginning