The Biology of Cancer Chapter 9:p53 and Apoptosis: Master Guardian and Executioner

Cell Death

Apoptosis Autophagy Necrosis

Programmedcell death.Death cycle isprogrammedby the cell itself

‘Self-eating’Catabolic processinvolving lysosomes.

‘Death’ causedby external factorslike trauma or toxins.Not programmed.

Cell Death

The term was originally used by Wyllie and his colleagues and is from the Greek meaning “dropping away” as the leaves from a tree.

Apoptosis: Programmed Cell DeathCell Suicide

The Face of Cell Death: Apoptosis

Active cell death• Specific gene expression• Specific intracellular signals • Requires energy and RNA and protein synthesis • Characteristic morphological features • DNA cleaved, chromatin condenses • Cells shrink • Formation of apoptotic body • Cleared by phagocytosis • No inflammation=no tissue damage

Passive cell death• Physical or chemical trauma• Cells swell up • Membrane breaks down and cellular contents leak out • Nucleus disintegrates • Cell ghosts • Inflammatory=tissue damage

Apoptosis Necrosis

Figure 9.18d The Biology of Cancer (© Garland Science 2007)

An apoptotic cellshowing fragmentedGolgi bodies (green)

Autophagy

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Autophagy: clearing out garbage

The Face of Cell Death: Apoptosis

Two Apoptotic Pathways: Extrinsic & Intrinsic

Two Pathways that Initiate Apoptosis

Intrinsic/ Mitochondrial Apoptosis Regulated by Mitochondrial Cytochrome C release

Extrinsic/ Death Receptor Apoptosis

Activated by ligation of Death Receptors Fas, TNF alpha These pathways intersect at the effector caspases

Two Pathways that Initiate Apoptosis

Intrinsic PathwayChemotherapyIrradiation

Figure 9.29 The Biology of Cancer (© Garland Science 2007)

The Apoptotic Caspase Cascade: ApoptosomeThe Wheel of Death

Pro-apoptotic signals openchannelsin the mitochondrialmembrane to allowcytchrome c andSmac/Diablo molecules to be released.Cytochrome cmolecules bind to Apaf1 toform theapoptosome. Theapoptosome activatespro-caspase 9 to caspase 9which in turnactivate caspase 3.Caspase 3 activatesin turn, a series ofexecutioner caspaseswhich cleave various deathsubstrateswhose cleavage creates theapoptoticcell phenotype.

Figure 9.28 The Biology of Cancer (© Garland Science 2007)

The Wheel of Death - Apoptosome

The apoptosomeis assembled in the

cytosol when cytochromec molecules are released

from the mitochondriainto the cytosol.

The apoptosome associates with Apaf1.

this causes the assemblyof the 7 spoked wheel

in which Apaf-1 forms the spokesand the cyt c forms the tips.

Once assembled this attractsprocaspase 9 into the

hub of the wheel which convertsprocaspase 9 into active caspase 9.

The resulting caspase 9proceeds in turn to cleave and

activate other caspase moleculesthereby triggering the apoptotic

cascade.

Caspase 9 is activated

Caspase 9 activates the executioner caspases

Active caspase 9

Executioner caspases :Caspase 3, 6 & 7 cleave

DNA by activatingDNAase

APOPTOSIS

Executioner caspases :Caspase 3, 6 & 7 cleave DNA

by activating DNAase

APOPTOSIS

Caspase 9 is activated

Caspase 9 activates the executioner caspases

Mitochondrial Cyt C release

INTRINSIC APOPTOTIC PATHWAY

The Extrinsic Pathway: Inthe extrinsic pathway, signalmolecules known as ligands,which are released by othercells, bind to transmembranedeath receptors on the targetcell to induce apoptosis. Forexample, the immunesystem’s natural killer cellspossess the Fas ligand(FasL) on their surface. Thebinding of the FasL to Fasreceptors (a death receptor)on the target cell will triggermultiple receptors toaggregate together on thesurface of the target cell. Theaggregation of thesereceptors recruits an adaptorprotein known as Fas-associated death domainprotein (FADD) on thecytoplasmic side of thereceptors. FADD, in turn,recruits caspase-8, aninitiator protein, to form thedeath-inducing signalcomplex (DISC). Throughthe recruitment of caspase-8to DISC, caspase-8 will beactivated and it is now ableto directly activate caspase-3, an effector protein, toinitiate degradation of thecell.

The extrinsic apoptotic pathway

The Extrinsic Apoptotic Pathway

Disc (death inducing signal complex)

TRADD : tumor necrosis factor death domain, FADD: Fas associated death domain.

Cleaves DNA

Figure 9.19 The Biology of Cancer (© Garland Science 2007)

Apoptosis of cells forming webs between future mousetoes. The dark dots are apoptotic cells.

Apoptotic humor !

p53 and Apoptosis

Figure 9.8 The Biology of Cancer (© Garland Science 2007)

p53 - activating signals’s and p53 downstream effects

A variety of cellphysiologic stressescan cause a rapidincrease in p53 levelswhich proceeds toinduce a number of responses.

A cancer cell does not want to undergo apoptosis hence it initiates

anti-apoptotic strategies

Figure 9.34 The Biology of Cancer (© Garland Science 2007)

Anti-apoptotic strategies used by cancer cells

Cancer cells resort tonumerous strategiesin order to decrease thelikelihood of apoptosis.This diagram indicates thatin various cancercell types the levels oractivity of importantpro-apoptotic proteinsare decreased (blue).

Conversely, the levels oractivity of certainanti-apoptotic proteinsmay be increased (red).

Figure 9.37 The Biology of Cancer (© Garland Science 2007)

The Apoptotic Circuit Board

The full array of components governing apoptosis is notknown. An initial attempt at modeling the system is shown.

Cancer cells invent numerous ways to inactivate the apoptotic machinery in order to survive

Among these are the activation of Akt pathway,inactivation of p53 and also inhibition of caspases

Loss of apoptotic functions allows cancer cellsto survive a variety of cell physiological stresses

such as DNA damage