Mechanisms of Cell Death: Apoptosis, Autophagy, and Necrosis Flashcards Preview

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Flashcards in Mechanisms of Cell Death: Apoptosis, Autophagy, and Necrosis Deck (98):
1

Programmed cell death

-i.e. death by suicide

Apoptosis

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Catabolic process involving the degradation of a cell's own components through the lisosomal machinery

-i.e. Death by self-cannibalism

Autophagy

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Defined as the premature death of cells by external factors

-i.e. Death by accident or murder

Necrosis

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Most of what we know about apoptosis was discovered in

C. elegans

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An integral part of both plan and animal tissue development

Apoptosis

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In C. elegans, out of 1090 somatic cells, 131 of them underwent apoptosis. The different cells died at different times in

-remarkably accurate

Development

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In normal development, apoptosis is required for

Tissue sculpting

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Apoptosis is important in the immune system after infection for for eliminating used

T and B cells

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A balance between proliferation and cell death is required to maintain

Tissue homeostasis

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Crucial for eliminating cells that have been damaged by UV, radiation, chemical toxins, or viral infection

-i.e. it can prevent cancer

Apoptosis

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An example of apoptosis function during tissue development is the development of the

Fingers and toes

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Problems in apoptosis during finger and toe development results in

-2 or more fingers/toes are joined together

Syndactily

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Lack of apoptosis during embryo development also disrupts

Normal brain development

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Humans who are born with tails have deficiencies in

Apoptosis

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What are five morphological markers of apoptosis?

1.) Electron dense nucleus
2.) Nuclear fragmentation
3.) Large, clear vacuoles
4.) Blebs at the surface
5.) Loss of cell adhesion

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What is one very common biochemical marker of apoptosis?

Phosphatidylserine flipping from inner leaflet to outer leaflet

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Phosphatidylserine flipping from inner leaflet to outer leaflet enables

Apoptotic cells to enter cell

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Enables us to track nicks in DNA

Terminal Transferase dUTP Nick-End Labeling (TUNEL)

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Used to add labeled dUTP to 3' terminal end of the DNA fragments

Terminal Transferase

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Highly sensitive and can detect fewer than 100 cells

-Fast: can be completed in 3 hours

TUNEL Assay

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Has high reproducibility with good precision

TUNEL Assay

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One of the disadvantages of TUNEL Assays are that we don't know the minimum number of strand breaks necessary for detection. Thus we may miss the

Early stages of apoptosis

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Designed to detect apoptotic cells that undergo extensive DNA degradation during the late stages of apoptosis

-Based on the ability of dUPT to label blunt ends of double-stranded DNA breaks independent of a template

Terminal Transferase dUTP Nick-End Labeling (TUNEL Assay)

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Can generate false positives in a TUNEL assay

Necrotic cells

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Another disadvantage of a TUNEL assay is that the detergent used to permeabilize cells can make them

Frgile

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A distinctive feature of DNA degraded by caspase-activated DNAse (CAD)

DNA laddering

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Cleaves genomic DNA at internucleosomal linker regions, resulting in DNA fragments that are multiples of 180-185 bps in length

Caspase-activated DNAse (CAD)

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Must be cleaved to become active

Caspases

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What are the two major apoptotic pathways?

1.) Cell-extrinsic pathway
2.) Cell-intrinsic pathway

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The key enzymes that give rise to all of the morphological and biochemical changes arising from apoptosis

Caspases

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What are the two types of apoptotic caspases?

1.) Initiator (apical) caspases (#'s 2, 8, 9, and 10)
2.) Effector (executioner) caspases (#'s 3, 6, and 7)

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Regulated at a post-translational level, ensuring that they can be rapidly activated

Caspases

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What are the steps of the caspase cascade?

Pro-apoptotic stimulus ---> initiator caspases ---> effector caspases ---> apoptosis

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Initiator caspase is activated by

2 proteolytic cleavages

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Initiator caspase then cleaves and activates

Effector caspase

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Cleaves nuclear lamins, inhibitors of DNAases, and Actin

Effector Caspases

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The intrinsic apoptosis pathway is also known as the

Mitochondrial mediated pathway

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The extrinsic apoptosis pathway is also known as the

Death receptor mediated pathway

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Family of proteins that regulates the integrity of the mitochondrial membrane

BCL2

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What are the two pro-apoptotic BCL2 proteins?

BAX and BAK

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What are the three anti-apoptotic BCL2 proteins?

BCL2, BCL-XL, and MCL1

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The regulators/sensors of the intrinsic pathway are "BH3-only proteins" and include

BAD, BID, and PUMA

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Characterized by permeabilisation of the mitochondria and release of cytochrome c into the cytoplasm

Intrinsic apoptotic pathway

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Forms a multi-protein complex known as the ‘apoptosome’ and initiates activation of the caspase cascade through caspase 9

Cytochrome C

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Cytochrome C activates

-activates caspase 9

Apoptotic protease activating factor 1 (APAF1)

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Antagonism of BCL2 causes the activation of the BAX/BAK channel which causes the mitochondria to release

Cytochrome C

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Responsive to DNA damage by UV radiation

-one of the most studied genes of all time

p53

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Can activate DNA repair proteins, arrest cell at G1/S checkpoint, and initiate apoptosis

p53

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p53 is a transcription factor that regulates

Cell cycle and apoptosis

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Acts as a ubiquitin ligase and covalently attaches ubiquitin to p53, thus marking it for degredation

Mdm2

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Also transports p53 from nucleus to cytosol

Mdm2

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The critical event leading to the activation of p53 is

Phorphorylation of its N-terminus

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The protein kinases known to target this transcriptional activation domain of p53 can be broken down into what two groups?

1.) Members of MAPK family
2.) Checkpoint kinases

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Oncogenes also stimulate p53 activation, mediated by the protein

p14ARF

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Contains many pro-apoptotic proteins such as cytochrome C

Mitochondria

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Can be release from the mitochondria in response to pro-apoptotic signals

Cytochrome C

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Translocate to the mitochondrial membrane and stimulate the formation of pores allowing Cytochrome c to leak out

-normally found in the cytosol

Pro-apoptotic molecules (i.e. Bad, Bax, Bid)

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Interacts with APAF-1 to form the apoptosome

Cytochrome C

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Interaction between cytochrome C and APAF-1 activate

-promotes caspase cascade

Caspase 9

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Promote apoptosis by tying up Bcl2 and freeing Bax/Bak

Bid and Bad

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Binds Bax/Bak and prevents pore formation

-anti-apoptotic

Bcl-2

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Promote pore formation, release of cytochrome C and APAF1, and initiation of apoptosis

Bax and Bak

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Results from a chromosomal translocation between the 14th and 18th chromosomes, which places the BCL-2 gene next to the IgG heavy chain locus

Follicular Lymphoma

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The fusion gene of BCL-2 and IgG heavy chain leads to

High expression of BCL-2

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High expression of BCL-2 then results in a decreased propensity of cells for undergoing

Apoptosis

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Occurs in several cancers and is linked to poor disease outcome

Increased Bcl-2 protein expression

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Triggered by the p53 tumor-suppressor in
response to DNA damage and other types of severe cell stress

Intrinsic pathway

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Conventional anticancer therapies, such as chemotherapy, activate the intrinsic pathway via

p53

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p53 activates the intrinsic pathway through transcriptional upregulation of pro-apoptotic members of the BCL2 family of proteins such as

PUMA and Bax

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The extrinsic apoptotic pathway is apoptosis via the pro-apoptotic receptors

DR4 and DR5 (Fas receptors)

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Activate the pro-apoptotic receptors DR4 and DR5

Endogenous Apo2L/TRAIL

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The activated pro-apoptotic receptors D4 and D5 then recruit

Fas-associated death domain (FADD)

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Recruits initiator caspase 8 and/or 10 to the death-inducing signaling complex (DISC)

FADD

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The DISC activates caspases 8 and 10 and releases them into the cytoplasm, where they activate

Caspases 3, 6, an 7

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Triggers apoptosis in response to the activation of pro-apoptotic receptors, such as DR4 and DR5, by specific pro-apoptotic ligands, such as Apo2L/TRAIL

Extrinsic apoptotic pathway

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The extrinsic apoptotic pathway stimulates apoptosis independently of

p53

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Ligand-induced activation of DR4 and DR5 leads to the rapid assembly of the death-inducing signaling complex (DISC) and the recruitment of initiator caspases 8 and 10 through the adaptor

Fas-associate death domain (FADD)

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The extrinsic and intrinsic apoptosis pathways converge on

Caspases 3, 6, and 7

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Also, caspases 8 and 10 (extrinsic) activate Bid,which activates

Bax and Bak (intrinsic)

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Responsible for degrading cellular proteins and organelles and recycling them

-A survival pathway

Autophagy

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Autophagy is actually a response to

Cellular starvation

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Occurs in many disease states, including cancer, inflammatory bowel disease, and neurodegenerative disorders

Disregulation of Autophagy

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The sequestration of cellular organelles into cytoplasmic autophagic vacuoles (autophagosomes) that fuse with lysosomes and digest the enclosed material

Autophagy

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What are the four stages of autophagy?

1.) Induction
2.) Autophagosome formation
3.) Autophagosome-lysosome fusion
4.) Autophagosome breakdown

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A key regulator of autophagic induction is

-has an inhibitory affect

mTOR (mammalian target of rapamycin)

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A serine-theronine kinase

mTOR

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Many of the genes that are upregulated in response to mTOR deactivation participate in

Autophagosome formation

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Involves formation of a membrane around a targeted portion of the cell

Autophagosome formation

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In autophagosome-lysosome fusion, the autophagosome fuses w/ the lysosome releasing its contents into the lysosome for

Degredation by proteases

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Inevitably breaks down the autophagosome

Lysosome

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Has contrasting roles during cancer development, progression, and treatment

Autophagy

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Typically caused by factors external to the cell or tissue, such as infection, toxins, or trauma

Necrosis

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Unlike apoptosis and autophagy, is almost always detrimental and can be fatal

Necrosis

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What are the five types of necrosis?

1.) Coagulation necrosis
2.) Liquefactive necrosis
3.) Enzymatic fat necrosis
4.) Caseous necrosis
5.) Gangrenous necrosis

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Cell destruction leading to escape of hydrolases

Liquefactive necrosis

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Typically begins with cell swelling, chromatin digestion, and disruption of the plasma and organelle membranes

Necrosis

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Charactrized by extensive DNA hydrolysis, vacuolation of the endoplasmic reticulum, organelle breakdown, and cell lysis

Late necrosis

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What is the cause of inflammation in necrosis?

Release of intracellular contents after plasma membrane rupture

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