3 diseases where autophagy plays a specific role?
talks with?
Huntington’s disease, prion diseases, and breast cancer treated with tamoxifen.
cross talk with apoptosis.
Explain the extrinsic pathway of apoptosis, including two different starting proteins: 4
- Either Fas Receptor or TNFR binds Fas ligand on other cells or TNF-α
- Receptor oligomerizes (multimerizes), which allows “Death Domains” to recruit adaptor proteins FADD or TRADD that have “death effector domains”
- FADD or TRADD recruit caspase 8, which also have “DED” that bind to the “DED”s of the FADD or TRADD
- These Caspase 8s are now activated which then activate effector caspases, such as CASPASE 3.
- nuclear breakdown, blebbing, phosphatidyl serin–phagocytosis
How are initiator caspases activated?
two precursor caspases come into close proximity, and then they activate each other.
How do initiator caspases activate effector caspases?
They activate “procaspases” by cleaving off the pro domain. The procaspase becomes an activated effector caspase.
What do effector caspases specifically do? (start with cleaving something in cell)
- Cleave lamins, and destroy DNA
- Chromatin condensation and Ca++ influx
- cytoplasmic blebs
- Blebs become apoptotic bodies as cell shape changes w/actin degradation
- Flips phosphatidylserine to the outside, making eat me signal for cytoplasmic blebs to be eaten
Explain the process of intrinsic apoptosis, starting when the process is inhibited. 4
- anti-apoptotic proteins BCL-2 and BCL-x2 bind to pro-apoptotic proteins BAX and BAK, which inhibits their function.
- BH3 only proteins such as BAD and BIK (called sensitizers) bind to the anti-apoptotic proteins, which then allows BAX and BAK to bind to each other
- BH3 only proteins such as BID and BIM (called activators) assist in the dimerization of BAX and BAK to form a pore in the mitochondria.
- The mitochondria can then release ions, and then cytochrome C and Apaf-1 (together make apoptosome
- The apoptosome recruits and activates the initiator caspases, caspase 9.
- They then activate effector caspases, such as caspase 3
- —so BLC-2 proteins regulate cyto c relaease from mito
How can the extrinsic pathway also start the intrinsic pathway?
Caspase 8 from the extrinsic pathway can activate a precursor of the BH3 activator protein called “BID,” which then starts the intrinsic pathway.
- What is anoikis?
2. Important in what pathology? Why?
- Special type of apoptosis that occurs when cells detach from ECM.
- Important in development of tumor metastasis. This is because the cells would have to detach from the ECM to metastasize, but this would induce anoikis. They must survive/overcome/inactivate anoikis to live.
Explain the steps/reasoning behind anoikis:
- When integrin is attached to trophic factor, Akt Kinase phosphorylates BAD, inactivating it.
- If trophic factor/ECM is not attached to integrin,(decrease in P1-3 kinase) this can’t happen. Thus, BAD can help with intrinsic apoptosis by making proapoptotic proteins
What is the unfolded protein response, how does it work?
Important in what?
Unfolded/misfolded proteins in the ER (ER stress) is sensed by BiP chaperone protein. Protein synthesis is thus inhibited. Prolonged activation of UPR leads to apoptosis via caspase 12, which leads to activation of caspase 9.
Diabetes and neurodegenerative disorders, as well as viral infection.
What is the biggest difference between apoptosis and necrosis?
Necrosis shows breakdown of membrane integrity;
Cells swell, plasma membrane collapses, and inflammation results
3 different times we generally see necrosis? example with heart? How can you tell how much necrosis?
toxic agents, ischemia, and hypoxia.
In a myocardial infarction. Releases myocardial specific enzymes, and relative level indicates how much.
Explain reperfusion injury with myocard. infarction
Once blood flow is restored to tissue, inflammatory mediators cause build up of ROS and NO species. These lead to additional necrosis.
What decides which type of cell death is used? What order?
Depends on amount of damage, as well as extent of mitochondria permeability.
Small amount of damage would being autophagy, while more would be apoptosis. extreme would be necrosis, although necrosis and apoptosis can happen in the same place simultaneously.
what proteins are the BH3 only proteins? What is their general function?
BAD BIK BID BIM
pro-apoptotic.
Family of proteins in the intrinsic pathway that regulate apoptosis?
Bcl-2 proteins.
are anti-apoptotic proteins tumor suppressors or proto-oncogenes?
proto-oncogenes.
