2 Life and Death
2.5.2 c ell d eath By a PoPtosis (P rograMMed c ell d eath )
Apoptosis.is.the.genomically.regulated.form.of.cell.death.that.permits.the.safe.elimination.of.
senescent.or.damaged.cells.when.they.have.fulfilled.their.intended.biological.functions.or.have.
been.damaged.in.certain.ways..It.is.also.known.as.programmed cell death.(PCD)..Examples.of.
PCD.can.be.found.throughout.the.eukaryote.animal.and.plant.kingdoms..Apoptosis.is.neces-sary.for.embryonic.development.in.animals.and.normal.replacement.of.tissues.in.adult.life..Its.
dysregulation.in.humans.can.result.in.oncogenic,.inflammatory,.autoimmune,.and.neurodegen-erative.diseases.[Hajra.&.Liu.2004]..Infectious.agents,.including.viruses,.can.exploit.apoptosis.
in.the.host.to.evade.the.immune.system..A.simplified.schematic.diagram.of.the.complex.apop-totic.biochemical.pathways.in.a.eukaryotic.cell.is.shown.in.Figure.2.7..The.broad.arrows.should.
be.interpreted.as.“causes”.or.“leads.to.”.Many.other.molecular.pathways.have.been.omitted.for.
simplicity.
When.a.cell.is.induced.to.undergo.apoptosis,.it.shrinks..It.then.develops.bubblelike.blebs.on.
its.outer.membrane..The.genomic.material.(DNA.and.histones).in.its.nucleus.is.broken.down..Its.
mitochondria.also.break.down,.releasing.the.protein.cytochrome c..The.phospholipid,.phosphati- dylserine,.which.is.normally.hidden.within.the.plasma.membrane,.is.exposed.to.the.surface..Phos-phatidylserine.is.bound.by.receptors.on.phagocytic cells (e.g.,.macrophages.and.dendritic.cells).
that.ingest.the.cell.fragments..The.phagocytic.cells.of.the.immune.system.secrete.cytokines.(e.g.,.
Interleukin-10.and.TGF-β).that.inhibit.the.immune.system’s.inflammatory.response.
Under.what.conditions.do.cells.undergo.apoptosis?.The.answer.is,.“under.many.conditions.”.
PCD. is. necessary. in. normal. embryological. development.. Some. examples. include. the. metamor-phosis.of.Lepidoptera.(a.caterpillar.changes.to.a.butterfly),.the.resorption.of.the.tadpole’s.tail.as.it.
metamorphoses.into.a.frog,.the.removal.of.tissue.webs.between.the.fingers.and.toes.of.a.fetus,.and.
the.resorption.of.excess.or.irrelevant.neural.connections.(synapses).in.the.developing.brain.
Other.examples.of.normal,.programmed.apoptosis.include.the.constant.turnover.of.adult.epi-thelial.cells.in.the.skin,.the.constant.replacement.of.cells.in.the.lining.of.the.stomach.and.gut,.the.
replacement.of.olfactory.sensory.cells,.and.the.periodic.replacement.of.endometrial. cells.in.the.
uterus.following.menstruation.
Apoptosis.is.also.needed.to.destroy.cells.that.represent.a.threat.to.survival.of.the.organism..
When.cells.are.infected.with.viruses,.the.viruses.can.leave.fragments.of.their.coat.proteins.on.the.
host.cell.surface..These.signs.of.infection.are.recognized.by.cytotoxic T lymphocyes.(CTLs),.which.
induce.the.newly.infected.host.cells.to.undergo.PCD.before.they.can.produce.new.viruses..Once.
an.infection.is.cleaned.up.by.the.immune.system,.the.excess.immune.system.cells.themselves.are.
removed.by.CTLs,.which.also.induce.PCD.in.each.other.and.in.themselves.[Kimball.2004b]..It.
should.be.clear.that.such.a.cascade.of.PCD.must.be.very.strictly.regulated.
Cells. with. DNA damage. also. undergo. PCD.. DNA. damage. can. come. from. many. external.
sources,.such.as.ionizing radiation.(gamma,.alpha,.and.neutrons),.heat,.UV.radiation,.and.oxidizing.
chemicals..It.can.have.a.host.of.bad.effects,.including.the.development.of.cancer.and.birth.defects..
Cells.respond.to.DNA.damage.by.increasing.their.production.of.the.transcription factor protein.
p53,.a.potent.inducer.of.apoptosis.[Kimball.2007d,e;.Whitmarsh.&.Davis.2000]..Ionizing.radiation.
and.certain.antimetabolite.drugs.are.used.on.cancerous.cells.in.hopes.of.damaging.them.to.the.point.
of.inducing.their.PCD.mechanism.
The.mechanisms.of.cell.apoptosis.are.triggered.by.the.shift.in.a.balance.between.positive sig-nals.(i.e.,.the.need.for.continuing.survival).and.the.input.of.negative signals.that.induce.PCD..Some.
examples.of.positive.signals.are.the.presence.of.Interleukin-2 (IL-2),.an.essential.factor.for.immune.
system.lymphocyte.proliferation.and.growth,.and.neural growth factor..Negative.signals.include.
increased.levels.of.oxidants.within.the.cell,.DNA.damage.(see.preceding.text),.and.accumulation.of.
proteins.with.bad.tertiary.structures.(this.could.be.the.result.of.gene.damage)..The.presence.of.PCD.
activator.molecules.include:.tumor necrosis factor alpha.(TNF-α),.which.binds.to.the.TNF.recep-tor.(TNFr);.lymphotoxin.(aka.TNF-β), which.also.binds.to.the.TNFr;.and.Fas ligand (FasL),.a.
Introduction to Molecular Biology, Genomics and Proteomic for Biomedical Engineers
Cellmembrane Fas/Apo-1
Casp-8
WD-40 repeat (WDR) region
Cytochrome c
Caspase-9
(To nucleus) CED-4 “arm”
Bak Bid
Cell stress
Mitochondrion
p53 Damaged DNA
Bax
AIF Apoptosis
(Caspase -3, -6, -7) ER stress
Apoptosome
(The “chopper”) Apaf-1
Fas
Fas ligand
Procaspase-9
figuRe . (See.color.insert.).A.schematic.overview.of.some.of.the.molecular.pathways.leading.to.apoptosis.in.eukaryotic.cells..The.seven-spoked.apoptosome.
molecular.complex.is.shown.
molecule.that.binds.to.a.cell.surface.receptor.protein.called.Fas.(aka.CD95)..FasL can.be.expressed.
on.cell.surfaces.along.with.Fas.
There.are.three.different.mechanisms.leading.to.PCD.[Kimball.2004b]:
. 1..One.triggered.by.signals.internal.to.the.cell.
. 2..A.second.initiated.by.cell death activators.binding.to.certain.cell.surface.receptors,.which.
include.TNF-α,.TNF-β,.and.Fas.
. 3..A.third.that.may.be.triggered.by.dangerous.oxidizers.inside.the.cell,.which.cause.molecu-lar.damage.
Let.us.first.examine.the.internal,.mitochondrial PCD pathway..In.a.healthy.cell,.the.outer.mito-chondrial.membranes.have.the.surface.receptor.protein.Bcl-2..Bcl-2 in.turn.is.bound.to.the.protein.
apoptotic protease-activating factor-1 (Apaf-1)..Internal.damage.to.the.cell.(e.g.,.from.oxidizers).
causes.Bcl-2 to.release.Apaf-1 and.a.related.protein,.Bax..Apaf-1 and Bax penetrate.the.mitochon-drial.membranes.and.cause.the.enzyme.cytochrome c.to.leak.out.into.the.cytosol..The.released.
cytochrome c and Apaf-1 bind.to.form.a.seven-spoked.multimeric.molecular.complex.(see. Fig-ure.2.7),.the.center.of.which.binds.to.seven.molecules.of.procaspase-9..This.wheel-like.molecular.
complex.is.known.as.the.apoptosome..Somehow,.a.molecular.signal.activates.the.procaspase-9.in.
the.apoptosome.to.form.caspase 9 [Zou.et.al..1999]..(Note.that.some.13.different.caspases.have.
been.identified.in.cells.).Caspase 9 is.an.enzyme.specialized.in.cleaving.proteins,.generally.at.an.
aspartic acid.AA..When.caspase 9 cleaves,.it.activates.other.caspases.in.an.expanding.cascade.of.
proteolytic.activity.that.leads.to.digestion.of.the.cell’s.enzymes.and.structural.proteins.in.the.cyto-plasm,.thence.to.degradation.of.chromosomal.DNA,.apoptosis,.and.ultimately.to.phagocytosis.of.
the.cell.by.other.cells.such.as.immune.system.macrophages..(See.the.paper.by.Hill.et.al..[2003].for.
a.good.description.of.the.caspases.and.the.apoptosome;.a.glossary.of.the.many,.many.abbreviations.
and.acronyms.used.to.describe.the.molecules.in.the.regulatory.pathways.of.apoptosis.can.be.found.
at:.www.biosource.com/content/apop/glossary.html.)
There.are.other.intracellular.proteins.in.the.Bcl-2.family..Bcl-2.and.Bcl-XL.by.themselves.tend.
to.inhibit.apoptosis,.at.least.partly.by.blocking.the.release.of.cytochrome c.from.mitochondria..
Other.members.of.the.Bcl-2.family.are.not.PCD.inhibitors.but.instead.promote.procaspase.acti-vation,.leading.to.apoptosis..Some.of.these.PCD.promoters.such.as.Bad.function.by.binding.to.
and.inactivating.the.PCD-inhibiting.members.of.the.family,.whereas.others.such.as.Bax and.Bak.
stimulate.the.release.of.cytochrome c.from.mitochondria..If.the.genes.encoding.Bax.and.Bak.are.
inactivated,.cells.are.remarkably.resistant.to.most.apoptosis-inducing.signals..This.indicates.the.
importance.of.these.two.proteins.in.apoptosis.control..Bax and Bak are.themselves.activated.by.
other.apoptosis-promoting.members.of.the.Bcl-2.family,.such.as.Bid..Clearly,.these.relations.are.
extremely.complex.and.are.only.now.beginning.to.be.understood.
Another.important.family.of.PCD.regulators.is.the.IAP.(inhibitor.of.apoptosis).family.of.pro-teins..It.belongs.to.a.specialized.group.of.proteins.called.E3 ubiquitin protein ligases.that.trans-fer.ubiquitin.protein.“labels”.onto.caspases,.thereby.blocking.PCD..IAPs.are.thought.to.inhibit.
apoptosis.in.two.ways:.(1).They.bind.to.some.procaspases.to.prevent.their.activation,.and.(2).they.
bind.to.caspases.and.inhibit.their.activity..IAP.proteins.were.first.discovered.as.being.produced.by.
certain.insect.viruses.(the.host.cell.produces.them.from.the.viral.genome)..They.prevent.the.host.
cell.from.killing.itself.before.the.virus.has.had.time.to.fully.replicate..When.mitochondria.release.
cytochrome c.to.activate.Apaf-1,.they.also.release.a.protein.that.blocks.IAPs,.thus.greatly.expedit-ing.the.PCD.process.
The Ubiquitin-Proteosome Pathway (UPP).is.the.principal.mechanism.for.protein.catabolism.
in.a.eukaryotic.cell’s.cytosol.and.nucleus. This.pathway.is.highly.regulated.and.affects.a.wide.vari- ety.of.cellular.processes.and.substrates..Defects.in.the.UPP.can.result.in.the.pathogenesis.of.sev-eral.important.human.diseases..Hershko,.Ciechanover,.and.Rose.received.the.2004.Nobel.Prize.in.
Chemistry.for.their.work.on.elucidating.the.UPP..The.UPP.is.important.in.a.wide.variety.of.cellular.
Introduction to Molecular Biology, Genomics and Proteomic for Biomedical Engineers processes..It.is.involved.in.regulating.cell.mitosis,.DNA.repair,.the.biogenesis.of.cell.organelles,.
immune.response.and.inflammation,.antigen.processing,.modulation.of.cell.surface.receptors,.ion.
channels.and.the.secretory.pathway,.embryogenesis,.the.regulation.of.transcription,.endocytosis,.
and.of.course,.apoptosis..We.shall.consider.the.latter.application.here.
Ubiquitin.(Ub).is.a.small.(76.AA).protein.found.only.in.eukaryotic.cells..(However,.Ub-like.
proteins.are.also.found.in.Eubacteria.and.Archaea.).The.Ub.AA.sequence.is.highly.conserved.along.
the.eukaryotic.evolutionary.tree.branches..For.example,.there.is.only.a.three-AA.difference.in.the.
Ub.from.yeast.to.humans..Ub.is.found.throughout.the.cell.and.can.exist.in.free.form.or.complexed.
with.other.proteins..Ub.functions.to.regulate.protein.turnover.in.a.cell.by.regulating.the.break-down.of.specific.proteins..This.regulatory.role.is.important.because.by.quickly.destroying.a.protein.
(enzyme).that.regulates.another.function,.it.can.change.the.rate.of.a.chemical.reaction.in.the.cell.
and.also.the.expression.of.specific.genes..It.does.not.destroy.proteins.itself;.it.serves.as.a.molecular.
tag. to. mark. a. protein. that. will. be. destroyed. through. ATP-dependent. enzymatic. hydrolysis. by. a.
specialized.protein.complex,.the.proteosome..Special.E1, E2,.and.E3.enzymes.(many.types.of.each.
exist),.using.energy.supplied.by.ATP,.attach.Ub.to.a.protein.selected.to.be.destroyed..The.E1.and.
E2.enzymes.also.catalyze.the.attachment.of.Ub.molecules.to.itself.by.covalent.bonding,.forming.
short.Ub.chains.that.are.attached.to.the.“victim”.protein..A.“library”.of.E3.proteins.(Ub-ligases).is.
responsible.for.victim.selection.for.Ub.tagging..When.Ub tags.onto.a.protein,.it.is.called.ubiquitina-tion or.ubiquitinylatags.onto.a.protein,.it.is.called.ubiquitina-tion. To.underscore.the.complexity.of.the.UPP.system,.special.deubiquitinylat-ing.enzymes.are.involved.in.unbinding.Ub.from.proteins.and.disassembling.Ub.chains.
Once.obsolete.or.unnecessary.proteins.are.tagged.with.at.least.four.Ub.molecules,.they.are.
destroyed.by.the.large,.about.1,000.kD,.proteins.called.the.26S.proteosomes. The.process.is.shown.
schematically.in.Figure.2.8..A proteosome.is.a.very.efficient.molecular.protein.shredder,.but.its.
destructive.machinery.is.guarded..So,.it.cannot.run.amok.in.the.cell.and.destroy.useful.proteins;.
it.needs.the.four.Ub.molecules.to.work..What.is.not.known.well.are.all.the.signals.used.by.the.E-enzymes.in.selecting.their.victim.protein.molecule.and.how.the.signals.work..There.is.evidence.that.
the.N-terminal.AA.of.a.protein.may.send.one.signal;.it.has.been.called.the.N-degron.
Certain.AA.sequences.in.the.victim.appear.to.be.degradation.signals..The.“PEST”.sequence.
is.one.such.signal..PEST.stands.for.proline,.glutamic.acid,.serine,.and.threonine..One.example.of.
PEST.regulation.of.protein.destruction.is.the.transcription.factor,.Gcn4p,.which.has.281.AAs..Its.
PEST.sequence.is.found.at.positions.91–106..The.normal.half-life.of.this.protein.is.about.5.minutes..
However,.if.only.the.PEST.sequence.AAs.are.removed,.the.half-life.increases.to.about.50.minutes,.
a.tenfold.increase..Signals.to.tag.a.protein.with.Ub.may.also.lie.buried.in.the.hydrophobic.core.of.
the.folded.molecule..This.is.why.partially.folded.or.abnormal.proteins.may.be.more.prone.to.degra-dation..An.important.question.is,.how.do.the.E3-proteins.“recognize”.an.abnormality.as.such?.Is.it.
because.a.PEST-like.AA.sequence.that.signals.“tag.for.death”.is.exposed.to.the.E-complex?
The. core particle (CP). of. a. proteosome. complex. is. cylindrical. in. shape;. its. active. sites. are.
hidden.inside.the.tube..The.outside.of.the.proteosome.does.not.induce.hydrolysis.of.proteins;.it.is.
biochemically.benign..The.two.molecular.“caps”.on.the.ends.of.the.proteosome.CP.regulate.entry.
of.the.victim.protein.into.the.center.hydrolysis.chopping-chamber..The.victim.protein.is.reduced.
to.pieces.from.3.to.23.AAs.in.length,.which.are.further.broken.up.by.other.enzymes,.and.the.free.
AAs.are.“recycled”.in.the.cell’s.metabolism.to.make.new.proteins..The.core.particle.is.made.of.
a.stack.of.four.rings;.each.ring.is.made.from.seven.protein.subunits.(not.unlike.the.apoptosome’s.
“wheel”)..The.regulatory particle (RP) molecules.cover.each.end.of.the.core.particle..Each.RP.is.
made.of.14.(!).different.protein.subunits.(none.of.the.same.as.used.in.the.CP)..Six.of.these.proteins.
are.ATPases,.and.some.subunits.recognize.(have.affinity.for).ubiquitin..(ATPase.is.an.enzyme.that.
cleaves.the.two.outer.phosphate.bonds.on.ATP,.releasing.the.chemical.energy.in.the.bonds.to.drive.
other.biochemical.reactions;.AMP.is.the.result.)
Clearly,. there. must. be. a. delicate. balance. between. the. normal. destruction. of. ubiquitinylated.
proteins. in. a. cell. and. the. mass. destruction. of. cell. proteins. by. caspases. in. the. apoptosome.. The.
UPP.process.is.clearly.not.apoptosis.but.can.contribute.to.apoptosis..A.major.question.that.must.
be. answered. is,. how. do. Ub,. the. E-proteins,. and. the. proteosome. interact. with. caspases. and. the.
apoptosome?
According.to.Friedman.and.Xue.[2004]:.“The.proteosome.appears.to.play.an.important.role.
in.suppressing.inadvertent.activation.of.proapoptotic.proteins.in.cells.that.need.to.live,.and.par-ticipates.in.eliminating.anti-apoptotic.proteins.in.response.to.apoptotic.stimuli..After.the.initiation.
of.apoptosis.and.the.activation.of.caspases,.the.proteosome.is.then.disabled.to.allow.the.build-up.
of.proapoptotic.proteins,.which.tilts.the.balance.of.life.and.death.further.toward.the.point.of.no.
return”..[Quoted.with.permission.]
External signals can also trigger the PCD pathway..Recall.that.the.cell’s.surface.membrane.has.
the.integral.membrane.receptor.proteins, Fas.and.TNFr, embedded.in.it..(An.Fas.receptor.is.shown.in.
Figure.2.7.).When.the.external,.complementary.death activator proteins (FasL.and.TNF-α or TNF-β,.respectively).bind.to.these.two.receptors,.the.event.triggers.a.signal.into.the.cytoplasm.that.activates.
caspase 8,.which,.similar.to.caspase 9,.initiates.a.cascade.of.proteolytic.activity.that.ends.with.the.
death.and.phagocytosis.of.the.cell..Note.that.some.11.highly.regulated.caspases.have.been.recognized.
in.human.cells..They.normally.are.dormant.and.have.to.be.activated.to.kill.cells.from.within.
Neurons.can.undergo.PCD.without.the.aid.of.caspases..Apoptosis-inducing factor.(AIF).is.a.
protein.normally.located.in.the.intermembrane.spaces.of.mitochondria..When.the.neuron.receives.
its.“time-to-die”.signal,.this.leads.to.AIF.being.released.(not.unlike.the.triggered.release.of.cyto-chrome c.in.the.first.PCD.pathway)..An.AIF.complex.migrates.to.the.cell’s.nucleus.where.it.binds.
to.the.DNA.and.triggers.its.destruction..Cell.death.follows..The.DNA.is.ultimately.chopped.into.
oligos.as.small.as.200.bps..It.has.been.shown.that.in.vitro,.massive.potassium.loss.from.the.neuron.
Catalytic core (20S) Other
proteases
Oligopeptides
Regulatory cap (19S) β subunit
α subunit E2
E3
Ubiquitated protein substrate AAs
26S Proteasome
+
+
E2
E1 (Deconjugation)
Conjugation process
Ubiquitin +ATP
Protein to be destroyed
figuRe . (See.color.insert.).Schematic.illustrating.the.pathway.where.a.protein.tagged.by.polyubiquitin.
is.broken.down.by.a.proteosome.
0 Introduction to Molecular Biology, Genomics and Proteomic for Biomedical Engineers cytosol.is.associated.with.apoptosis..Blocking.potassium.channels.in.the.neuron.membrane.with.
tetraethylammonium.(TEA).reduced.the.rate.of.neuron.PCD.[Sage.1997].
Some.pathogens.contain.a.means.of.blocking.apoptosis.so.that.the.infected.cells.do.not.do.PCD.
and. remain. as. “hosts,”. allowing. the. pathogen. to. replicate.. According. to. Kimball. [2004b],. some.
viruses.that.cause.cancers.use.molecular.“tricks”.to.prevent.apoptosis.in.the.cells.they.have.trans-formed..For.example,.the.human.papilloma virus.(HPV).has.been.implicated.in.causing.cervical.
cancer..It.produces.a.protein.(E6).that.binds.to.and.inactivates.the.critical.apoptosis promoter pro-tein,.p53..The.Epstein-Barr virus.(EBV).is.the.cause.of.infectious.mononucleosis.and.is.associated.
with.some.lymphomas..Once.inside.their.host.cells,.EBVs.produce.a.protein.similar.to.Bcl-2.and.
also.induce.the.cell.to.make.more.of.its.own.Bcl-2.apoptosis.inhibitors..Melanoma.(a.dangerous.type.
of.skin.cancer)-transformed.cells.avoid.apoptosis.by.inhibiting.the.expression.of.the.gene.encod-ing.Apaf-1..Lung.and.colon.cancer.cells.secrete.elevated.levels.of.a.“decoy”.molecule.that.binds.to.
FasL,.blocking.it.so.that.it.cannot.bind.to.Fas.receptors.on.the.cancer.cell.that.trigger.PCD..More.
FasL.molecules.are.produced.at.the.surface.of.a.cytotoxic T-lymphocyte.(CTL).of.the.immune.sys-tem.when.it.binds.to.a.cancer.cell’s.altered.cell.surface..Normally,.this.excess.FasL.would.bind.to.the.
cancer.cell’s.Fas.receptors.and.trigger.its.PCD..However,.the.decoy.molecules.from.the.cancer.cell.
inactivate.the.FasL.molecules..As.a.further.tribute.to.the.“cleverness”.of.cancer.cells,.we.note.that.
other.types.of.cancer.cells.secrete.excess.FasL,.which.can.bind.with.the.CTL’s.own.Fas.receptors,.
causing.it.to.undergo.apoptosis..(Note.that.the.CTL.is.somehow.protected.from.its.own.FasL.) The.body’s.use.of.FasL.to.actively.prevent.PCD.of.certain.tissues.is.seen.in.“immunologically.
privileged.sites,”.which.include.the.anterior.chamber.of.the.eye.and.the.testes..High.densities.of.
FasL.bound.on.the.surfaces.of.the.target.cells.kill.any.CTLs.that.draw.near.to.it..Because.the.FasL.
is.bound,.it.cannot.bind.to.the.cell’s.own.Fas.receptors.(good.thing).
In HIV/AIDS,.the.HIV.virions.infect.a.few.of.one.type.of.their.target.host.cells,.the.CD4+ T-lymphocytes.of.the.immune.system..Far.more.CD4.cells.die.than.are.virally.infected;.the.cause.is.
apoptosis..HIV-infected.CD4.cells.express.an.HIV.gene.that.makes.a.protein,.Nef,.which.causes.the.
infected.cell.to.make.high.densities.of.membrane-bound.FasL.at.its.surface.which.cannot.bind.with.
its.own.Fas.receptors,.preventing.the.infected.cell.from.undergoing.PCD..However,.when.the.HIV-infected.CD4+.cell,.which.is.bristling.with.virally.induced.FasL,.encounters.another.uninfected.
lymphocyte.closely,.the.uninfected.cell’s.Fas.binds.to.the.infected.cell’s.FasL,.and.the.uninfected.
CD4+.cell.undergoes.apoptosis..Removal.of.its.host.cells.by.this.mechanism.actually.works.against.
the.HIV.virus,.but.it.surely.kills.its.host.animal.(if.untreated).by.weakening.its.immune.system!
In.conclusion,.we.note.that.apoptosis,.or.PCD,.relies.on.a.highly.regulated,.complex,.interactive.
biochemical.system.with.multiple.inputs..PCD.is.necessary.for.normal.embryonic.development.and.
the.maintenance.of.a.healthy.mature.animal.or.plant..PCD.is.also.a.very.active.medical.research.
topic..If.we.can.learn.to.manipulate.its.complex.biochemical.control.systems,.we.may.find.an.effi-cient.means.of.fighting.cancer.by.inducing.the.PCD.of.cancer.cells.alone..The.HIV.also.can.produce.
abnormal.stimulation.of.apoptosis.in.certain.immune.system.cells..Perhaps.that.can.be.blocked,.
inhibiting.the.release.of.HIV.virions.
Organ.transplant.rejection.is.also.due.to.transplant.cell.apoptosis.induced.by.the.host’s.CTLs.
and.other.immune.cells..A.cell’s.normal.UPP.system,.which.is.concerned.with.internal.protein.