Lecture 9: Stem Cells & Apoptosis Flashcards
Stem Cells
Show continuous growth throughout life
Precursors for mature, differentiated cell production
Multipotent and can develop into any number of specialized cells depending on environmental cues
(Basal layer of epidermis, Hematopoietic cells)
Postmitotic Cells
Reach highly differentiated state and usually do not divide
Neurons, Skeletal muscle, Cardiac muscle
Quiescent Cells
Cells that reach mature differentiated state and do not divide under normal circumstances
Will divide under extraordinary circumstances (Liver cells)
Properties of stem cells
Self-renewal
Proliferation
Differentiation
Housed in niches maintained by surrounding stroma cells
What are stroma cells?
Connective tissue support in which the parenchyma is located
What is the parenchyma?
Masses of tissues similar in type, mostly epithelial derived
Teratoma
Neoplasm composed of multiple tissues
Embryonic stem cells
Derived from embryonic inner cell mass
Can give rise to all tissue types (except placenta)
Adult stem cells
All stem cells other than embryonic
More limited in developmental potential
How is cell growth controlled?
By density-dependent inhibition
What is density-dependent inhibition?
Cells grow as far as they physically can (in culture dish with edges)
Can be overcome by addition of growth factors or lowering cell density
Lost in neoplastic cells
Cells stop dividing after ~50 mitotic cycles
What does senescent mean?
Cell has reached its 50 cell cycles
Telomeres
Ends of chromosomes that become shorter with each cell division
Telomerase maintains length of telomeres
T/F: The telomeres on cancer cells get shorter quicker than normal cells.
False, the telomeres on cancer calls don’t get shorter allowing them to divide in greater number
Define apoptosis
Process of cell death in which cells are genetically programmed and/or signaled to self-destruct in such a way that inflammatory processes are not activated
What is apoptosis used for?
Elimination of…
Webbing between digits during development
Unnecessary portion of reproductive system once gender identified
Cells during hormone withdrawal
Cells with damaged DNA due to radiation of chemotherapy
Immature lymphocytes
Infected cells during viral infection
T/F: The cells are degraded from the inside out
True
What is necrosis?
Contents of cell released following breakdown of membranes
Induced by external insults
More likely to activate inflammatory mechanisms
What are the 3 phases of apoptosis?
Recognition of unbalanced/damaged cell
Execution
Elimination
What are the 2 pathways of apoptosis?
Extrinsic pathway & Intrinsic pathway
How is the extrinsic pathway activated?
By external factors binding to “death” receptors
How is the intrinsic pathway activated?
By leakage of mitochondrial proteins into cytoplasm
Describe caspases
Exist as inactive “procaspases”
Consist of 4 subunits (2, p10’s & 2, p20’s)
Describe procaspases
Consist of 2 subunits (p10 & p20)
Bind to receptor via CARD on N-terminal via p20
What activates the upstream initiator caspases?
Cell-death signal (Fas ligand or tumor necrosis factor-alpha)
What do initiator caspases activate?
Downstream caspases (executioners)
What procaspases do the executioner caspases contain?
3, 6, & 7 and have N-terminal called DED (death-effector domain)
Explain the first 5 steps of the “Fas Pathway”
1) Apoptotic-inducing ligand
2) Paracrine/autocrine mechanism
3) Fas binds to Fas receptor with intracellular domain
4) Fas receptor is trimerized
5) Trimerized Fas recruits FADD (Fas-associated protein with death domain)
Explain steps 6-10 of “Fas Pathway”
FADD binds to death domain
FADD recruits procaspase 8 via CARD
8) Procaspase 8 is converted to activated caspase 8
9) Caspase 8 = death-inducing cell signaling complex (DISC)
10) Caspase 8 (upstream initiator) activates procaspase 3
Explain steps 11-13 of “Fas Pathway”
11) Caspase 3 (downstream executioner) cleaves Bid
12) Bid translocates into mitochondria and releases cytochrome c
13) Caspase 3 cleaves ICAD (inhibitor of caspase-activated DNAase)
Explain steps 14-17 of “Fas Pathway”
14) Cleaved ICAD releases CAD which moves into nucleus to break down DNA
15) Induction of DNA fragmentation/inhibition of repair
16) Release of apoptotic bodies
17) Macrophages phagocytize apoptotic bodies
Explain first 4 steps of “Bax Pathway”
1) Bax, Bak, Bid, & Bad are proapoptotic proteins
2) Bcl-2 is antiapoptotic protein that prevents Bax from punching holes in mitochondrial membrane
3) Bax/Bcl-2 maintain [equivalent]
4) Bax gets upper hand and punches hole in mitochondrial membrane releasing cytochrome c into cytoplasm
Explain steps 5-8 of “Bax Pathway”
5) Cytochrome c + Apaf-1 + SIMPS –>apoptosome–>activation of procaspases
6) Induction of DNA fragmentation/inhibition of repair
7) Release of apoptotic bodies
8) Macrophages phagocytize apoptotic bodies
What does Apaf-1 stand for?
Apoptosis protease activity factor-1
What does SIMPS stand for?
Soluble intermembrane proteins
What is apoptosis-inducing factor (AIF)?
Located in intermembrane mitochondrial space
Can leak into cytoplasm
Migrates to nucleus
Binds to DNA and triggers fragmentation
T/F: AIF triggers apoptosis in the absence of caspases.
True
Where does the endosomal-lysosomal pathway occur?
In the secondary lysosome
Where does the procaspase-caspase pathway occur?
In they cytosol
What is the Ubiquitin-26S pathway and where does it take place?
Takes place in the cytosol
Has 2 steps:
1) Attachment of ubiquitin to protein substrate
2) Degradation of target protein by 26S proteasome
