This is a summary of Molecular Biology of Cancer chapter 7-14. This is the perfect summary to prepare yourself for the second exam in the Oncology course. It contains figures and detailed explanations.
SUMMARY OF
PECORINO’S MOLECULAR BIOLOGY OF CANCER
Chapter 7: Apoptosis
Apoptosis:
- Highly regulated process of cell death (suicide), such as the peeling of your skin after
a sunburn.
- Phagocytosis cleans up the results and caspases play a role in initiating apoptosis.
- Characterized by membrane blebbing, cell shrinkage and budding. Unlike necrosis,
which makes the cell leaky, and the contents of a cell spill out in the environment.
7.1 Molecular mechanisms of apoptosis
Apoptosis induction:
- By extracellular signs: death factors
- By intracellular signs: chemical insults such as DNA damage or oxidative stress.
- Caspases are molecular scissors to cleave intracellular proteins at aspartate resides.
They are inactive when made and should be cleaved at their own aspartate residues
to be activated.
Extrinsic pathway:
- Death receptors play a role, such as Fas ligand or TNF (tumor necrosis factor). TNF is
soluble and Fas is bound to plasma membrane. When ligands are bound to death
receptors, a conformational change occurs to transduce the signal downstream. This
change exposes death domains that are located intracellularly and enable adaptor
proteins such as FADD and TRADD. These transduce death signals from receptors to
caspases (specifically procaspase 8). Procaspase 8 molecules self-activate and then
caspase 8 is activated. These molecules all together are called DISC (death-inducing
signalling complex). Caspase 8 cleaves 3, 6 and 7.
- Inhibition of this pathway can happen through c-Flip, which can inhibit FADD binding
or caspase-8 recruitment and activation.
- Breakdown of cells results from proteolysis, such as nuclear laminas. Caspase
activated DNase cleaves chromatin and nucleosomes. Caspases cleave RB, too, which
is required for TNF apoptosis.
Intrinsic pathway:
- Stimuli from inside the cell activate the intrinsic pathway through Bcl-2 proteins.
o One group Bcl-2 inhibits apoptosis and the other promotes it. All Bcl-2
proteins have BH domain to interact with proteins. BH3-only proteins contain
only a BH3 domain and induce pro-apoptotic molecules or bind and inhibit to
anti-apoptotic Bcl-2 proteins. The anti-apoptotic proteins bind pro-apoptotic
to accumulate them away and inhibit apoptosis.
, Isabella Ghauharali
- The permeabilization of the mitochondrial membrane and release of pro-apoptotic
factors triggers the intrinsic pathway. The intermembrane space of mitochondria is a
cabinet basically for mediators.
o MOMP: mitochondrial outer membrane permeabilization happens by Bcl-2 in
the intermembrane space. Then, Bim and Bid activate Bax by binding.
Through a conformational change in Bax it locates to the mitochondria to
insert in the membrane and dimerize. This increases permeability because it
forms pores from which cytochrome c can leak. BH3 domain of Bax is needed
for apoptotic activity and interactions with anti-apoptotic proteins (BclX
dissociates Bax dimers).
o Then, cytochrome c binds to Apaf-1 and together with procaspase-9 and ATP
it forms the apoptosome. CARD domains recruit more procaspase 9. Apaf-1 is
needed to activate procaspase-9. Then caspase 3, 6 and 7 are activated.
o XIAP is an apoptosis inhibitor and binds active caspase 3 and 7 by binding to
their active site. NF-B induces apoptosis inhibitors.
Smac/DIABLO inhibit the inhibitory function of IAPs.
Crosstalk between extrinsic and intrinsic pathways:
- Caspase 8 is usually active in extrinsic pathway, but can cleave Bid (pro-apoptotic)
and that can stimulate the intrinsic pathway by activating Bax and Bak to release
cytochrome c.
P53 and apoptosis:
- P53 induces apoptosis in response to DNA and cellular stress. By transcription
dependent and independent ways. It transcribes death receptors and pro-apoptotic
members of Bcl-2 family. It can repress anti-apoptotic factors, too.
- P53 activation of Bax in cytoplasm is the transcription independent way. P53 can also
release sequestered proteins by Bcl-X. all these functions are linked by PUMA.
7.2 Apoptosis and cancer
Cancer:
- Avoidance of apoptosis allows for further accumulation of mutations. Oftentimes in
cancer the apoptotic pathway is defective.
- Apoptotic signals stimulate procaspase processing in normal cells, but in cancer cells
they stimulate the cessation of IAP inhibition of processed caspases. Cancer cells
contain activated caspases, but there is an upregulation of IAPs, so they cannot
become properly active.
TRAIL receptors:
- Subfamily of TNF receptors
- TRAIL ligand induces apoptosis in cancer cells, but not in normal cells. This does
happen in a similar way to TNF receptor apoptosis.
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