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Lecture notes and subexam 2 Oncology
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Lecture notes for exam 2 for the Oncology course (chapters 7 to 14).
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Deeltentamen 2: OncologyChapter 7: Apoptosis
Examples of exam questions
DNA damage induces apoptosis via
A. Caspase 9 activation,
B. Induction of p53 expression
C. Caspase 3 activation
D. All three of the above mentioned answers are correct
Briefly explain how triggering of apoptosis in tumor cells can contribute to new therapies
against cancer and give an example of a therapy.
Apoptosis: is the regulated and orderly destruction of a cell through a genetically encoded
process also known as programmed cell death (PCD). Apoptosis is a type of ‘’cell suicide’’
that is intrinsic to the cell. Important for tumor suppression because it gets rid of cells that
have extensive DNA damage which potentially leads to cancer.
Apoptosis is organized, neat, and tidy, leaving behind little evidence of the preexisting cell.
The cell undergoing apoptosis is swept clean during phagocytosis by macrophages,
neighboring cell that recognize molecular flags (phosphatidyl serine).
A: necrotic cell
B: top -> normal cell and bottom -> cell going through apoptosis
wherein the chromatins are condensation.
C: a necrotic cell with lesions
D: an apoptotic cell blebbing
Function of apoptosis:
Active ATP dependent process
Physiological in many organs:
- Developmental morphogenesis: during embryogenesis (fingers are developed etc.) and
apoptosis is important in the development of fingers. When this is not going well →
fingers are not separated enough.
- Controls cell numbers: balance of cell numbers is important.
- Removal of damaged cells:
- Negative and positive selection of lymphocytes:
- Cytotoxic effect of radio- and chemotherapy: treatment of cancer.
, 2.2 kg cells per day: died as result of apoptosis.
Apoptosis Necrosis
Cell shrinkage Cell swells
Membrane bledding and Leaky membranes
budding
Organelles intact Organelles damaged
Apoptotic bodies Cell lyses
Chromatin condensation Chromatin damaged
and precise fragmentation
No inflammation Inflammation
In A zie je een lymfocyt,
deze herken je door de grote
kern met een dun laagje
plasma eromheen. In D
condensation of the
chromatin. In F you see the
that the nucleus is falling out
in swears, and than in
apoptotic bodies which are
recognized by the
macrophages.
By necrosis you see holes in
the cell and you see bladders in apoptosis.
Especially proteases and caspases are important in
apoptosis.
- Proteolysis: catalyzed by caspases help break
down cellular components for the neat disposal that is
characteristic of apoptosis.
Apoptosis signaling
• Induction of apoptosis
- Programmed
- Loss of growth factors, of adhesion
- Death receptors of the TNFR family
- T- and B cell antigen receptors
- CTLs
- DNA damage (irradiation, chemotherapy)
- Stress conditions
• Mitochondrial changes
• Activation of the caspase family
• Proteolytic cleavage of structural and functional proteins
, • Induction of apoptosis morphology
Apoptosis induced by: extracellular signals ‘’death factors’; or by internal
physical/chemical (DNA damage or oxidative stress)
Caspases
- This are cysteine-asparate-proteases synthesized as zymogens
- Act like molecular scissors to cleave intracellular proteins or asparate residues.
- Requirement for an aspartatic acid at the P1 position
- 14 family members cloned
- Caspases 2,3,6,7,8,9 and 10 are involve
in apoptosis
- Divided into
• Initiators: 2,8,9 and 10
• Effectors: 3,6, and 7
• Inflammatory: 1,4 and 5
Synthesized as inactive enzymes -> called pro-
caspases that needs to be cleaved as asparate
residues in order to be activated.
In the figure, you see the changes which must be
done for activation.
Thus, cleavage of the asparate residues -> activation -> caspases can activate each other
very easily. This leads to an apoptotic signal. Only a few caspases have to be activated
for apoptosis.
ASP; specific amino sequences
which must be removed for
activation.
QACxG = is bepalend voor welk
soort caspase het is.
Four apoptosis pathways:
1. Intrinsic/stress-induced or mitochondrial apoptosis pathway
2. Extrinsic/death receptor mediated apoptosis pathway
3. Granzyme B mediated apoptosis pathway (inflammatory diseases)
4. ER mediated apoptosis pathway
Two major apoptosis pathways!!
, Intrinsic pathway
P53 stabilization in the nucleus → BH3 only proteins are activated → translocation of Bas
and Bax from the cytoplasm to the mitochondria → cytochrome C release → cytochrome
can in the presence of ATP and Apaf-1 form a complex with pro-caspase 9 → Active caspase
9 can activate caspase 5/6/7 → apoptosis
Extrinsic pathway
1. A death receptor such as the FAS ligand binding or
tumor necrosis factor (TNF) is received by a
transmembrane death receptor such as the FAS
receptor or the TNF receptor.
2. Ligand binding -> conformational change -> form
homotrimers
3. Expose a ‘’death domain = purple square’’ which
enables intracellular adaptor proteins such as FADD
and TRADD to bind via their death domains.
4. Activate pro-caspase 8 via their death effector
domains (purple triangles) which bring them close to
each other and then become activated by self
cleavage.
5. DISC: the ligands, receptors, adaptors and initiator
caspase together called.
6. One activated caspase cleaves and activated other
caspases -> called: executioner caspases (caspase
3/6/7)
7. Finally, cleavage of a specific protein -> resulted in apoptosis.
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