Week 5 -pt.2

Question 1

Syndactyly

Answer 1

Webbing of digits does not go away due to lack of apoptosis during development

Question 2

Final stage of apoptosis

Answer 2

During blebbing, flipases send phosphatidyl serine to the outer membrane. THis is recognized by macrophages, and macrophages phagocytosis blebs.

Question 3

Caspases

Answer 3

Proteases that degrade hundreds of cellular targets during apoptosis.

Question 4

some examples of diseases of excessive apoptosis

Answer 4

Viral infections (AIDS)

Neurodegenerative diseases (Alzheimer’s and Parkinson’s)

Acute CNS insult (stroke)

Ischemic injury (heart, kidney)

Toxin induced diseases (alcohol induced brain and liver damage)

Question 5

Some examples of diseases of too little apoptosis

Answer 5

Autoimmune disorders-inability to remove self reactive immune cells.

Cancer- some are a result of loss of normal cell death mechanisms

Question 6

Bcl-2

Answer 6

Anti-apoptotic “survival” gene that is over expressed in human B-cell lymphoma.

Question 7

Bcl-2 family. Subgroups and functions.

Answer 7

Three subgroups depending on number of BH domains.

4 domains(Bcl-2)=anti-apoptotic 
3 domains (Bax,Bak) = pro-apoptotic
1 domain (BH3-only family, Bid, Bim, Bik)=pro-apoptotic

Bcl-2 inhibits Bak,Bax. Prevents apoptosis on a constitutive basis.

BH3-only proteins are activated (both transcriptional, and post translational activation including release from sequestration and phosphorylation)in response to cell stress. Inhibit Bcl-2, allowing Bak/Bax to initiate apoptosis.

Question 8

Bak/Bax method of function

Answer 8

Create channels in mitochondrial outer membrane to release cytochrome c (and other intermembrne space contents) to then activate caspases.

Question 9

Cytochrome c activation of caspases.

Answer 9

Seven molecules of apaf-1 (adaptor protein) combine with seven molecules of cytochrome c to form apoptosome wheel of death.

Apoptosome then recruits procaspase-9 which the becomes activated into caspases 9 (initiator)

Question 10

Effector caspases

Answer 10

3, 6, 7

Question 11

IAP

Answer 11

Inhibitor of apoptosis, protein that inhibits caspases

Question 12

Mac

Answer 12

Mitochondrial proteins that is released with cytochrome C to inactivate IAPs

Question 13

Non-caspases mediated cell death

Answer 13

AIF is released from mitochondrial intermembrane space with cytochrome c by Bax/Bak permeation.

Travels to nucleus to promote chromatin condensation and DNA fragmentation.

Question 14

Intrinsic Apoptosis pathway over view

Answer 14

pro-apoptosis signals and anti-poptotic signals compete to activate/deactivate BH3-only complexes-> inhibit Bcl-2-> free up Bak/Bax -> create channels in mitochondrial outer membrane-> release cytochrome c, Smac and AIF.

Cytochrome C + apaf-1 + procaspase9 complex forms up to activate executioner caspases (proteases)

Smac inhibits IAP’s to let caspases do job.

AIF travels to nucleus to start chromatin condensation and DNA fragmentation.

Question 15

Extrinsic apoptosis pathway

Answer 15

Death receptors bind to extracellular signal -> bind to intracellular Fas associated death domain-> activation of initiators procaspases 8 and 10

Caspases 8 activates effectors 3,6,7 and also activates Bid (BH3 family) to start mitochondrial mediated apoptosis

Question 16

Granzyme B mediated apoptosis

Answer 16

Granzyme B is a serine protease released by cytotoxic T cells and natural killer cells to cause apoptosis of virally infected cells.

Perforin is also released to aid entry of granzyme b

Granzyme B activate BH3 protein bid s well as caspases 3 and 8

Question 17

P53

Answer 17

Tumor suppressor. Mutations of this gene are present in about half of human cancers.

Expression is upregulated by multiple types of cell stress.

Can upregulate transcription of BH3 proteins to induce apoptosis

Promote activation of Bak and Bax

Promote transcription of death receptors

Question 18

Common necrosis etiologies

Answer 18

Ischemia is most common

Cancer, chemical (Hg, CN), metabolites of p450 (acetaminophen), infections (tuberculosis)

Question 19

Necrosis progression

Answer 19

Always starts with changes in membrane permeability (either mitochon, lysosome, or plasma) results in swelling and inflammation.

Nucleus breaks up and cytoplasm coagulates (shows up as anuclear, dark, dense cytoplasm in H+E stain)

Question 20

Pyknosis

Answer 20

Hyper condensation of nucleus during necrosis

Question 21

Karyorrhexis

Answer 21

Break up of nucleus during necrosis

Question 22

Karyolysis

Answer 22

Disappearance of nucleus during necrosis

Question 23

Coagulattive necrosis

Answer 23

Maintenance of cell/tissue shape, typical of ischemia, loss of nucleus.

Any organ except brain.

Question 24

Liquefactive necrosis

Answer 24

Release of enzymes that digest dead cells liquifies necrotic tissue.

Seen in brain, pancreas, abscesses

On stains we see a lot of debris and many inflammatory cels

Question 25

Caseous necrosis

Answer 25

Cheese like combination of liquifactive and coagulative necrosis. Typical of TB granulomatous inflammation and some fungi. On stains, characterized by large eosinophilic, multinucleated granulomatous cytoplasms.

Question 26

Fat necrosis

Answer 26

Calcium deposition causes saponification in necrotic fat heavy tissue (adipose, breast, pancreatitis).

Question 27

Fibrinoid necrosis

Answer 27

Necrosis of blood vessel walls. Fibrin leaks out of vessel. Seen in vasculitis and extreme hypertension.

Question 28

Outcomes of necrosis

Answer 28

Scarring, loss of organ function. Inflammation Calcification Autoimmune response Formation of ulcers and lesions