Lecture 6: Programmed Cell Death Flashcards
What is meant by “death is the default state”?
All cells are programmed to die, it is just the continuous stimulation via paracrine survival factors which prevents it
How can cell death occur?
lack of vital nutrients
lack of vital GFs
response to damage (physical or physiological)
What are the three main types of cell death?
- Necrosis
- Physiological programmed cell death (PCD) - including apoptosis
- Mitotic catastrophe
What is PCD/RCD?
“Physiological programmed cell death”
“Regulated cell death”
- Tightly regulated process in embryogenesis
- All multicellular organisms have mechanisms for killing their own cells for:
a. defence
b. development
c. homeostasis
d. ageing - Active process, req protein cleavage and in many cases ATP
What is apoptosis?
- Condensation of chromatin
- degradation in oligonucleosomal-sized fragments
- formation of plasma and nuclear membrane blebs 4. cell fragmentation into apoptotic bodies
- Rapid phagocytosis by neighbouring cells
What is autophagic degeneration?
- Autophagy: way of removing unwanted molecules/vesicles within a cell. HOWEVER can cause whole cell death
- Early appearance of lysosomes and autophagic vacuoles; cathepsins important
3.Limited DNA breakdown - Golgi & ER enlargement
- No inflammatory respons
- Beclin-1; key autophagy-promoting protein, often in reduced copy numbers in various human cancers
What is the process of autophagy?
- Stress activates JNK-1
- Formation of phagophore
- Beclin-1 bound to Bcl-2 is released upon Bcl-2 phosphorylation and binds to VPS34
- PI3K recruited, phagophore elongates and Atg proteins recruited
- LC3 inserted into membrane, autophagosome created, targets captured
- Fusion with lysosome
What is Entosis
- “cell death as a result of becoming engulfed by a neighbouring cell”
- Not a phagocytotic process, but req force production from actin/myosin cytoskeleton
- Internalized cell is viable in short term, occasionally they can extricate or be expelled from the cell.
- Cells are degraded via lysosomes.
- Not apoptotic
What is pyroptosis?
- associated with anti-microbial responses during inflammation
- req caspase-1
- caspase-1 activated by large supramolecular complex termed “pyropsome”
What is necroptosis?
“Regulated necrosis”
chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injuries
What is aponecrosis?
“Chimeric cell death with both apoptotic and necrotic characteristics”
Morphological and biochemical exploration of a syncretic process of cell death sharing apoptosis and necrosis
What is mitoptosis
Programmed death of mitochondrion
What is the mitotic catastrophe?
Results as a combination of:
1. deficient cell cycle checkpoints (G2/M & M)
2. Cellular damage
Aberrant chromosome segregation.
Activation of caspase 2 and /or mitochondrial membrane permeabilization
How can you detect cells undergoing apoptosis?
- DNA ladder on agarose gel electrophoresis: “beads on a string” - DNA wound round histones
- TUNEL: in situ terminal deoxynucleotidyl transferase mediated dUTP nick-end labelling
- FACS: Fluorescence activated cell sorter
- Phosphatidylserine on cell surface (annexin 5) with propidium iodide
- Activated caspases (fluorescent substrates)
What is ANOIKIS?
“detachment induced apoptosis”
- signals from ECM are essential for the survival of many cell types
- Epithelial cells undergo apoptosis-like cell death when detached from the matrix, (CALLED ANOIKIS)
- Integrin mediated cell adhesion signals control the apoptosis machinery
- Integrin activation of focal adhesion kinase can suppress anoikis - via PI3K and Akt/protein kinases B
- Rho family GTPases Rac1 & Cdc42 important - dominant negative mutants mimic loss of anchorage
- Activation of Akt by matrix attachment (or oncogenic ras) protects cells from anoikis via phosphorylation of BAD
