Apoptosis Flashcards
- Describe characteristic plasma membrane, cytoplasmic, and nuclear events of apoptosis.
- Compare and contrast apoptosis and necrosis in terms of morphology, common triggers of the two phenomena, and relative importance in physiological and pathological processes.
- Name tissues in which there is most and least apoptosis. Suggest reasons for this difference.
- Describe the role of caspases in apoptosis, and discuss the role that the mitochondrion may play in the process. Identify the roles of Caspases 8, 9, and 3.
- Distinguish between the signaling of the intrinsic and extrinsic apoptosis pathways.
- Discuss the essential biological difference between phagocytosis of apoptotic and necrotic cells.
- Discuss the importance of apoptosis in tumor formation and progression.
- Describe a mechanism by which one cell can induce apoptosis in another cell, and give an example.
x
Apoptosis is classified based on _______.
Morphology
What happens in necrosis?
Mitochondria are the first organelle to fail. They swell. At the point called “high amplitude swelling,” they cannot maintain ATP production. Lack of ATP shuts down the Na/K transporter, the cell swells and bursts. The inflammatory response must be activated to eliminate the toxic byproducts of this explosion.
What is the defining morphological feature of apoptosis? What is the molecular basis of this morphology?
The defining morphological feature of apoptosis is a collapse of the nucleus. Chromatin becomes supercondensed, appearing as crescents around the nuclear envelope and, eventually, spherical featureless beads. The structural correlate of this morphological change is the fragmentation of DNA into units of one or several nucleosomes in length (multiples of 180)
Besides compaction of the chromatin, what 2 morphological changes occur? What happens next?
- cell shrinks remarkably in size (to 1/3)
- tears itself apart into apoptotic bodies
Engulfed by the phagocyte where it dies
What do flippase and scramblase do? When is each active?
Flippase is active in a healthy cell. It ensures that phosphatidylserine is restricted to the inner face of the pm. Scramblase is activated in an apoptotic cell, and it redistributes the PS in a 50/50 ration in/out.
Lymphocytes are the most radiation-sensitive cells in the universe; 0.05 grey will kill one by apoptosis, while it takes 150 grey to kill a macrophage. If lymphocytes are exposed to radiation in the presence of a drug that blocks transcription, they _____.
do not die. ►Conclusion: low-dose radiation does not kill lymphocytes; rather, it induces them to kill themselves.
[Actinomycin D experiment]
What is morphologic death?
Death of certain cells to shape the final form. Examples are death of cells in between the digits (destruction of webbing) and death of neurons which don’t form the proper connections early on).
Mitosis is estimated to occur 25 million times a second in an adult human. But using the 1 mitosis = 1 apoptosis assumption we find that, in an average adult, ___die every day
2 x 10^12 cells
What is the end point of both the extrinsic and intrinsic pathway of apoptosis?
Caspase 3 - the executioner
What is the overall philosophy of the intrinsic pathway?
Perturbation at the mitochondrial membrane, death controlled by pro- and anti-apoptotic Bcl-2 factors
[Normally the mitochondrial membrane is guarded by “anti-apoptotic” members of the Bcl-2 protein family, Bcl-2 and Bcl- XL. When the cell receives the suicide signal, “pro-apoptotic” members of the family such as Bim and PUMA are made; they move to the mitochondrion and replace Bcl-2 and Bcl-XL. This allows other members of the same family, Bax and Bax, to act on the membrane, ►making it permeable so it releases cytochrome C into the cytoplasm. That activates a cytoplasmic protein called Apaf-1. Finally, activated Apaf-1 activates ►the protease caspase-9, and it activates caspase-3, that eventually result in the classic appearance of apoptosis.]
What is the overall philosophy of the intrinsic pathway?
Cytotoxic (killer) T cells (CTL) are responsible for surveillance of the surfaces of all body cells. If a cytotoxic T cell recognizes that a cell is mutated or infected, it instructs the target cell to undergo apoptosis.
What are the two sub-pathways within the intrinsic (CTL) mode of apoptosis?
1) Signal transduction through Fas (CD95L) that recruits FADD–>Caspase-8—>caspase-3
2) In the other CTL mechanism, the killer cell secretes enzymes (granzymes) and a pore-making protein (perforin) that together deliver apoptosis-inducing molecules to its intended target.
How do viruses inactivate signal transduction through the Fas pathway?
By encoding v-FLIP. c-FLIP is a cellular protein that competes competitively with FADD for binding to caspase-8 . It is an apoptosis inhibitor. The balance between FADD and FLIP determines whether apoptosis succeeds or not.
[Amazingly, there are viral FLIPs (v-FLIPs), known from herpes viruses such as HHV-8, the Kaposi’s sarcoma virus. ]
Lymphocytes are more sensitive to radiation than any other cell. Why are lymphocytes so sensitive?
It may be because they are so dangerous. A very minor change in the environment—the binding of antigen to the cell’s receptor—can drive a lymphocyte into rapid cycle, so that the one cell can become 64,000 cells within 4 days. This poses a risk of autoimmunity, or even lymphoma.
►a damaged lymphocyte responds not by repair, but by committing suicide.
