BOC 134 lecture - 7 Cell Death

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

Executioner

Cell Death

Apoptosis Autophagy Necrosis

Programmed cell 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

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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



Srcf.ucam.org

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 open channels in the mitochondrial membrane to allow cytchrome c and Smac/Diablo molecules to be released. Cytochrome c molecules bind to Apaf1 to form the apoptosome. The apoptosome activates pro-caspase 9 to caspase 9 which in turnactivate caspase 3. Caspase 3 activatesin turn, a series of executioner caspaseswhich cleave various death substrateswhose cleavage creates the apoptoticcell phenotype.


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 activating DNAase



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: In the extrinsic pathway, signal molecules known as ligands, which are released by other cells, bind to transmembrane death receptors on the target cell to induce apoptosis. For example, the immune system’s natural killer cells possess the Fas ligand (FasL) on their surface. The binding of the FasL to Fas receptors (a death receptor) on the target cell will trigger multiple receptors to aggregate together on the surface of the target cell. The aggregation of these receptors recruits an adaptor protein known as Fas-associated death domain protein (FADD) on the cytoplasmic side of the receptors. FADD, in turn, recruits caspase-8, an initiator protein, to form the death-inducing signal complex (DISC). Through the recruitment of caspase-8 to DISC, caspase-8 will be activated and it is now able to directly activate caspase-3, an effector protein, to initiate degradation of the

cell.

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




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



Apoptotic humor !

p53 and Apoptosis


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


Anti-apoptotic strategies used by cancer cells

Cancer cells resort to numerous strategiesin order to decrease the likelihood of apoptosis.This diagram indicates that in various cancer cell types the levels or activity of importantpro-apoptotic proteins are decreased (blue). Conversely, the levels or activity of certainanti-apoptotic proteins may be increased (red).


The Apoptotic Circuit Board

The full array of components governing apoptosis is not known. 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

BOC 134 lecture - 7 Cell Death

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Transcript of BOC 134 lecture - 7 Cell Death