Cell apoptosis
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Apoptosis of biological signification For multicellular
organism, to maintain the integrity and balance, apoptosis is a
very important biological processes. (Summary)
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Essential part of life for every multicellular organism from
worms to humans. (Faddy et al.,1992)Apoptosis plays a major role
from embryonic development to senescence.
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History of cell death research
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necrosis() Programmed cell death,PCD Paraptosis
apoptosisautophagy)
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Cell death by injury-Mechanical damage -Exposure to toxic
chemicals Cell death by suicide -Internal signals
-External signals
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()necrosis Necrosis derived from Greek nekrosis,meaning
deadness. Necrosis is lethal cell injury or accidental cell death
in the living organism.
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Necrosis of the cells to change morphology
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DNA
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Kerr
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Apoptosis Cells in the fall as the leavesof the same death
Apoptosis derived from Greek apo,meaning away from, and
ptosis,meaning to fall.
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Apoptosis is needed for proper development
Why should a cell commit suicide?
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Apoptosis is needed to destroy cells Examples: Cells infected
with viruses Cells of the immune system Cells with DNA damage
Cancer cells
Why should a cell commit suicide?
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TT95%T
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programmed cell deathPCD
Apoptosis is a means to maintain the stability of the
environment from gene to control the cell's own death in an orderly
manner. Concept of apoptosis
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chromatinapoptotic body
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ATPDNA200bp
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DNA
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Summary :Apoptosis and necrosisApoptosisNecrosis
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Distinguish of necrosis and apoptosis
DNA
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Necrosis vs. ApoptosisCellular condensationMembranes remain
intactRequires ATPCell is phagocytosed, no tissue reaction
Ladder-like DNA fragmentationIn vivo, individual cells appear
affected
Cellular swellingMembranes are brokenATP is depletedCell lyses,
eliciting an inflammatory reaction DNA fragmentation is random, or
smearedIn vivo, whole areas of the tissue are
affectedNecrosisApoptosis
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Sydney Brenner, H. Robert Horvitz, John E Sulston 2002107,,
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Apoptosis: PathwaysDeath LigandDNA damage & p53Extrinsic
PathwayIntrinsic Pathway
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Fas1Fas(Fas receptor gene)
APO-1/CD95TNF
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2 Fas Fas ligand gene
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3(effect)FasFasFasFas
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FasFashomology trimers FasLFasFasFas forms trimers that are
activated when binding to FasL causes aggregation.
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Fas Fas Death domainDDFasLFasFasDDFADDDDFADDFas-associated death
domain
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FADDNDEDdeath effector domainCaspase-8-10DISC (death-inducing
signaling complex ) caspase-810caspasecaspase-3-6-7Caspase
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Extrinsic or cytoplasmic pathway TNFRFasRDR3DR4DR5pathway
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Ligand-induced cell deathThe death receptorsLigand-induced
trimerizationFasLTrailTNF
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Caspase Active site: CysteineCleavage site: Asparatic acid
Cysteine Asparatic acid specific proteaseAps-Xxx
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caspasecysteine aspartate-specific protease
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ICE-1 2ICE CED-3 Interleukin-1 -converting enzyme
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CED-3 caspase-367caspase-89caspasecaspase-8caspase-367
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A
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The caspase cascade involved in apoptosisProcaspase activation
by proteolytic cleavage.Caspase cascade
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Apaf-1 Apaf-1-1apoptotic protease activating factor-1ced-4
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Apaf-1CARDcaspase recruitment domaincaspase-9 ced-4 ATP/dATP
C/cApaf-1
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Apaf-1Caspase-3cApaf-2caspase-9Apaf-3Apaf-1/cATP/dATPApaf-1CARDcaspase-9caspase-3caspase
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MPT:
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Apoptosis: PathwaysDeath LigandsDNA damage & p53Extrinsic
PathwayIntrinsic Pathway
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Regulated mechanism of apoptosis
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stimulateinhibitAPOPTOSISBadBaxBidBikBcl-xSHrk+In the absence of
trophic factors, direct interactions between pro-apoptotic and
anti-apoptotic proteins lead to cell death. Most of those proteins
belong to the Bcl-2 family. Bcl-2Hcl-1Bcl-XlBcl-w-Induction and
Inhibition of ApoptosisBcl-2 Family
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Bcl-2Bcl-2ced-9c
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1-4Bcl-2BH1-4BH4BH3
Bcl-2
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anti-apoptoticBcl-2Bcl-xlBcl-wMcl-1pro-apoptoticBaxBakBadBidBimBH3BidBadBcl-2
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Bcl-2Bcl-XLMPTCyt.c AIF Bcl-2C Bcl-2Apaf-1caspase-91Bcl-2Bcl-2
Family & regulating functions
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p53GDNA
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DNADNA
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P53Bcl-2Bcl-2 P53 P53BaxNOXA PUMA Ccaspase P53Fas P53 p53 As a
transcription factor, p53 regulates downstream genes important in
cell cycle arrest, DNA repair, and apoptosis. After DNA damage, p53
holds the cell at a checkpoint until the damage is repaired. If the
damage is irreversible, apoptosis is triggered.
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Diseases associated to apoptosis deregulation
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Apoptosis inhibition 1. Tumor2Autoimmune diseases
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Apoptosis excess1.-FasRp53
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Measurement of morphology1 1
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(Hematorylin ,HE:2 -GiemsaWright
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2acridine orange, AO) HO 33342 (Hoechst 33342)HO 33258 (Hoechst
33258), DAPI DNADNAA-T
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rippledcreased
a
b
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3electron microscope cavitationsa
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4-Flow cytometry,FCMPropidium Iodide ,PI PI is membrane
impermeant and generally excluded from viable cells. PI is commonly
used for identifying dead cells. hoechst33342 DNAHoechs-PI
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PI
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Annexin V PI PS)VAnnexin VPSAnnexin VPSAnnexin VFITCPIPSPI
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Annexin V PIAnnexin VPIAnnexin V/PI
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DNA
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in situ end labelling technique,ISEL)TUNELTdTdUPT3-OH
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DNA
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