Chapter 18

Question 1

Name three causes for DNA damage - thing commonly considered cancerogenic

Answer 1

Smoking (chemical modification), radiation, e.g. UV from the sun (light/energy), DNA synthesis error

Question 2

Describe the DNA-damage-activated response that causes cell cycle arrest in G1

Answer 2

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.

Question 3

How does excess mitogens cause cell-cycle arrest or apoptosis?

Answer 3

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

Question 4

What are mitogens?

Answer 4

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

Question 5

What is a Caspase?

Answer 5

Protease that has a cysteine at its active site and cleaves its target proteins at specific aspartic acids

Question 6

What is an apoptosome?

Answer 6

Wheel-like assembly composed of seven copies of the Apaf1/cytochrome c complex

Question 7

What is apoptosis?

Answer 7

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

Question 8

What is death inducing signaling complex (DISC)?

Answer 8

An assembly of several proteins, including initiator caspases, on the cytosolic portion of the Fas death receptor

Question 9

What are the extrinsic pathway?

Answer 9

Apoptotic program triggered by the binding of an extracellular signal protein

Question 10

What is a survival factor?

Answer 10

Extracellular signal molecule that inhibits apoptosis

Question 11

What are the intrinsic pathway?

Answer 11

Apoptotic program that depends on the release into the cytosol of proteins from the mitochondrial intermembrane space

Question 12

What is a death receptor?

Answer 12

Cell-surface molecule that triggers apoptosis when bound by an extracellular signal protein

Question 13

What is an executioner caspase?

Answer 13

When cleaved by an initiator caspase, this protease is activated and participates in the widespread cleavage events that kill the cell

Question 14

Describe the intrinsic pathway of apoptosis?

Answer 14

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.

Question 15

What happens to mammalian cell that do not have cytochrome c?

Answer 15

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

Question 16

What blocks cytochrome c release?

Answer 16

Bcl1 proteins

Survival factors block apoptosis –> block release of cytochrome c

Question 17

What does a Fas ligand do?

Answer 17

Promotes apoptosis through a death receptor in the extrinsic pathway

Question 18

What is the role of Bcl12 anti apoptotic proteins?

Answer 18

Bind and inhibit the pro-apoptotic effector Bcl2 proteins like Bax and Bak

Question 19

What is the role of effector Bcl2 proteins?

Answer 19

Pro-apoptotic proteins. Form oligomers on the mitochondrial outer membrane to release cytochrome c and other proteins into the cytosol

Question 20

What is the role of BH3-only proteins?

Answer 20

“Pro-apoptotic” or “anti-anti-apoptotic”. Bind and inhibit anti-apoptotic Bcl2 proteins to relieve effector Bcl2 inhibition

Question 21

What is a decoy receptor?

Answer 21

Helps control apoptosis in heathy tissue

Bind to a ligand inhibiting the activation of a death receptor

Question 22

What is alkylation and how can it cause an apoptotic response?

Answer 22

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.

Question 23

What extracellular survival factors inhibit apoptosis?

Answer 23

Increased production of anti-apoptotic Bcl2 family protein

Inactivation of pro-apoptotic BH3-only protein

Inactivation of anti-IAPs

Question 24

Why is an immune response induced with necrosis, but not apoptosis?

Answer 24

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

Question 25

What is the immune response to pyroptosis?

Answer 25

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.

Question 26

Define apoptosis

Answer 26

The death of cells through autolysis which occurs as a normal and controlled part of an organism’s growth or development

Question 27

Define necrosis

Answer 27

The death of most or all of the cells in an organ or tissue due to disease, injury, or failure of the blood supply

Question 28

Define pyrotosis

Answer 28

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

Question 29

Explain the mechanism that blocks cell cycle progression during mitosis if a bipolar spindle is not correctly assembled

Answer 29

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.

Question 30

What are the consequences of spindle assemby bypass?

Answer 30

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.

Question 31

What is synthetic lethality?

Answer 31

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