Chapter 16: Apoptosis Flashcards
What is apoptosis?
Programmed cell death. cell suicide, cells digest themselves by activating a series of protease sand do not illicit any immune response.
Morphological features of Programmed cell death/suicide.
Is the mode of cell death occurring in a variety of other settings and has roles in normal homeostasis, inhibition of cancer, and disease processes.
Fragmentation of the cell and nucleus, blebbing of cell membrane, condensation of chromatin.
Which features appear in cells undergoing apoptosis but not in cells undergoing necrosis?
No cell spillage, no inflammatory response. The cell fragments are all contained in membranes.
- blebbing
- chromosome condensation
- DNA cleavage that appears as a ladder in DNA gels
How are initiator caspases activated?
d) Dimerization of two inactive initiator caspase monomers.
They are activated by dimerization and cleavage. One procaspase binds to the adapter protein, which calls another procaspase over to bind. When both initiator caspases bind, they dimerize and cleave. Once it’s cleaved it is activated and is an initiator caspase which then can go and activate executioner procaspase.
XIAP is an inhibitor of caspases. How does it work?
It binds to the loops on the caspase and prevent cleavage that would activate them.
It attaches to ubiquitin to caspases so they get degraded before they are active.
How are executioner caspases activated?
Activated initiator caspases cleave and activated executioner procaspases.
Which events does take place during the death receptor pathway of the tumor necrosis factor receptor (TNFR1) signaling?
- Binding of death ligands of TNF family to death receptors
- Death receptor ligation recruits adaptor proteins FADD via death domain DD.
- DED-DED interaction recruits initiator procaspase 8. They dimerize and are activated by induced proximity. The death inducing signaling complex DISC
- Activated caspase 8 leaves DISC and cleaves and activates executioner procaspases.
- Executioner caspases cleave substrate.
- Apoptosis
What is the complex found in the mitochondria that drives apoptosis?
Bax/bak and cytochrome c drive apoptosis.
n vertebrates most forms of apoptosis are triggered not by death receptors but by engaging the mitochondrial pathway of apoptosis. When this pathway is engaged, the outer membrane of the mitochondria becomes disrupted by bax/bak proteins that oligomerize on the outer membrane so that soluble unknown proteins in the mitochondrial intermembrane space diffuse into the cytosol. MOMP ( mitochondrial outer membrane permeabilization).
The release of these intermembrane proteins cause a cascade in the cell where apoptosomes are created, procaspase-9 is activated, then caspase 9 cleaves and activates executioner caspaces.
Explain how activation of tumor necrosis factor receptor (TNFR1) can induce antiapoptotic signals?
The ligation of TNFR 1 by TNF is capable of producing signals that both block and promote apoptosis. If NF-kb is activated, TNF fails to trigger apoptosis but instead participates in the inflammatory response. Alternatively, if NF-kb is blocked or if RNA or protein synthesis is inhibited, TNF triggers apoptosis.
What is the functional role of CARD domains?
The CARD domains of APAF-1 and procaspase 9 bind and activate the procaspase 9 that allows it to cleave and activate executioner caspases.
Death receptors share a death domain in the intracellular portion of the molecule. The death domains are another example of death folds, like CARD, DED and pyrin domains these interact with death domains in adaptor molecules.
MOMP, mitochondrial outer membrane permeabilization is a key event in apoptosis. What role do the apoptotic Bcl-2 proteins Bax and Bak play in MOMP?
c) Bax and Bak insert into the outer mitochondrial membrane, making it more permeable in some unknown fashion.
The activation and function of bax and bak are inhibited by the antiapoptotic member of the bcl-2 family. These bind to the activator proteins and prevent their function and also bind to active forms of bax and bak in this way antiapoptotic bcl-2 family members prevent MOMP and prevent apoptosis. (page 738) BAX and BAK are two multidomain proteins in the bcl-2 family these two proteins are responsible for MOMP and probably form the pores through which the proteins of the mitochondrial intermembrane space diffuse. BAX or BAK are induced to oligomerize in the mitochondrial membrane in the presence of a BH3-only protein such as BID.
During mitochondrial outer membrane permeabilization (MOMP) what is allowed to escape from the mitochondria?
Cytochrome C is released.
Soluble proteins in the mitochondrial intermembrane space diffuse into the cytosol where they interact with cytosolic proteins.
What is a complex of multimers of APAF-1 doing?
The complex of APAF-1 is called the apoptosome which recruits procaspase 9.
The cytochrome c that is released from the mitochondria binds to APAF-1 in the cytosol. This allows the dATP to bind to the APAF-1 so that it now exposed an oligomerization domain causing it to form a complex of 7 APAF-1 molecules called an apoptosome the center of which has exposed CARDs these bind to the CARD of an initiator caspase-9 the binding of the caspase-9 and the CARDs forces the caspases to dimerized thus activating them by induced proximity. The caspase-9 cleaves and activates executioner caspases leading to apoptosis.
How is procaspase 9 induced?
It is induced by proximity.
Procaspase 9 is induced via induced proximity when the CARD domain of procaspase 9 binds to the CARD domain of APAF-1.
How are Apoptotic cells completely removed from the tissue they reside in?
Phagocytes engulf the fragments of the apoptotic cells.
The removal of apoptotic cells from the body occurs by an active process. This occurs by phagocytosis (cell eating). DNA is chopped into small pieces for facilitated digestion cells fragment into bite sized morsels and the cell generates signals to solicit its engulfment. They also send eat me signals or find me signals.
Explain how death receptors activate initiator caspases.
Caspase-8 is activated upon ligation of death receptors, cleaves the BH3 only protein Bid resulting in it’s activation.
Death receptor ligation recruits adapter proteins FADD via the death domain. The DED-DED interaction with the FADD recruits the initiator procaspases where dimerization and cleavage causes activation by induced proximity.
