Chapter 18 Flashcards
DNA damage and cell death
Name three causes for DNA damage - thing commonly considered cancerogenic
Smoking (chemical modification), radiation, e.g. UV from the sun (light/energy), DNA synthesis error
Describe the DNA-damage-activated response that causes cell cycle arrest in G1
When DNA is damaged, various proteins are recruited to the site Nd initiate a signalling pathway causing cell cycle arrest
First kinase at the site is ATM or ATR
Chk1 and Chk are recruited and activated, resulting in phosphorylation of p53 This block binding to Mdm2, resulting in accumulation which stimulates the gene encoding p21
p21 binds and inactivates G1/S-Cdk and S-Cdk complexes, arresting the cell in G1.
How does excess mitogens cause cell-cycle arrest or apoptosis?
Abnormally high levels of Myc cause the activation of Arf, which binds and inhibits Mdm2 and thereby increase p53 levels.
Depending on the cell type and extracellular conditions, p53 then causes either cell-cycle arrest or apoptosis
What are mitogens?
A mitogen is a chemical substance that encourages a cell to commence cell division, triggering mitosis
Mitogenesis is the induction (triggering) of mitosis, typically via a mitogen
What is a Caspase?
Protease that has a cysteine at its active site and cleaves its target proteins at specific aspartic acids
What is an apoptosome?
Wheel-like assembly composed of seven copies of the Apaf1/cytochrome c complex
What is apoptosis?
Form of cell death that leads to fragmentation of the DNA, shrinkage of the cytoplasm, membrane changes, and cell death, without lysis or damage to neighboring cells
What is death inducing signaling complex (DISC)?
An assembly of several proteins, including initiator caspases, on the cytosolic portion of the Fas death receptor
What are the extrinsic pathway?
Apoptotic program triggered by the binding of an extracellular signal protein
What is a survival factor?
Extracellular signal molecule that inhibits apoptosis
What are the intrinsic pathway?
Apoptotic program that depends on the release into the cytosol of proteins from the mitochondrial intermembrane space
What is a death receptor?
Cell-surface molecule that triggers apoptosis when bound by an extracellular signal protein
What is an executioner caspase?
When cleaved by an initiator caspase, this protease is activated and participates in the widespread cleavage events that kill the cell
Describe the intrinsic pathway of apoptosis?
The intrinsic pathway can become activated by the expression or activation of pro-apoptotic factors (e.g., Noxa, Puma, Bad) that bind to and inhibit anti-apoptotic factors (e.g. Bcl-2 and Mcl-1).
These events activates the oligomerization of the pro-apoptotic factors Bak and Bax leading to the formation of pore structures in the outer mitochondrial membrane, the release of cytochrome c, assembly of Apaf 1 complexes, activation of caspases (procaspace-9 with CARD domain), and thereby the induction of apoptosis.
What happens to mammalian cell that do not have cytochrome c?
They are resistant to apoptosis induced by DNA damage.
DNA damage can only initiate intrinsic apoptosis, but without cytochrome c, the apoptosome cannot be assembled
What blocks cytochrome c release?
Bcl1 proteins
Survival factors block apoptosis –> block release of cytochrome c
What does a Fas ligand do?
Promotes apoptosis through a death receptor in the extrinsic pathway
What is the role of Bcl12 anti apoptotic proteins?
Bind and inhibit the pro-apoptotic effector Bcl2 proteins like Bax and Bak
What is the role of effector Bcl2 proteins?
Pro-apoptotic proteins. Form oligomers on the mitochondrial outer membrane to release cytochrome c and other proteins into the cytosol
What is the role of BH3-only proteins?
“Pro-apoptotic” or “anti-anti-apoptotic”. Bind and inhibit anti-apoptotic Bcl2 proteins to relieve effector Bcl2 inhibition
What is a decoy receptor?
Helps control apoptosis in heathy tissue
Bind to a ligand inhibiting the activation of a death receptor
What is alkylation and how can it cause an apoptotic response?
By targeting DNA
. Alkylation in the form of methylation is a common modification of DNA in cells, however, alkylation with longer chains are registered as DNA damage and induce intrinsic apoptosis.
What extracellular survival factors inhibit apoptosis?
Increased production of anti-apoptotic Bcl2 family protein
Inactivation of pro-apoptotic BH3-only protein
Inactivation of anti-IAPs
Why is an immune response induced with necrosis, but not apoptosis?
Apoptosis is controlled degradation of the cell in which the cell content is packed in apoptotic bodies which are engulfed by other cells. This way the immune system is not activated by the release of DNA, organelles and other cell material
What is the immune response to pyroptosis?
Pyroptosis may be initiated when an infection is registered.
The cell undergoing pyroptosis produce cytokines before rupturing which are signaling proteins that will activates the immune system to fight the infection.
Define apoptosis
The death of cells through autolysis which occurs as a normal and controlled part of an organism’s growth or development
Define necrosis
The death of most or all of the cells in an organ or tissue due to disease, injury, or failure of the blood supply
Define pyrotosis
Highly inflammatory form of programmed cell death that occurs most frequently upon infection with intracellular pathogens and is likely to form part of the antimicrobial response
Explain the mechanism that blocks cell cycle progression during mitosis if a bipolar spindle is not correctly assembled
a) The spindle assembly checkpoint (SAC) prevent metaphase-to-anaphase transition until all kinetochores on sister chromatids are correctly attached to the microtubule spindle apparatus
(1) Aurora B mediated phosphorylation that prevents the Ndc80 complex from stabilizing the interactions between microtubules and kinetochore proteins if the spindle is not bi-oriented
(2) binding of Mad1 and Mad2 to unattached kinetochores, which prevent cdc20 from activating the anaphase promoting complex.
Since the anaphase promoting complex is required for the subsequent events of ubiquitin-mediated degradation of securin, release of separase, cleavage of cohesion complexes, and segregation of sister chromatids, it will block cell cycle progression.
What are the consequences of spindle assemby bypass?
If the spindle assembly checkpoint is by-passed (e.g. by anti-cancer drugs) it might cause chromosome missegregation leading to aneuploidy, chromosome instability, and apoptosis.
What is synthetic lethality?
Synthetic lethality refers to two genetic loss-of-function events, either of which alone is compatible with viability, but together in the same cell result in lethality
