Block 3 Lecture 7 -- Growth Inhibition and Apoptosis Flashcards
What are signals for the intrinsic death pathway?
DNA damage, oxidative stress (radiation, toxin, hypoxia)
How is the intrinsic apoptosis pathway regulated?
by the Bcl-2 protein family
What are the subgroups of the Bcl-2 family?
1) proapoptotic (BH3-only, and non-BH3-only), 2) anti-apoptotic
What substances escape the mitochondira upon Bax penetration?
1) Cyto C, 2) Procaspase 9, 3) Smac/diablo
How does Bax insert into the mitochondrial membrane?
after complexing with 6-8 other Bax
What are the components of the apoptosome?
oligomers of cyto c + procaspase 9 + apaf-1
What is apaf-1?
co-factor for procaspase 9 activation normally found in the cytosol
How are procaspase 9s activate?
NOT by simple close proximity; need Apaf-1
What is smac/diablo?
mitochondrial protein that inhibits IAB
What is IAP?
inhibitor of apoptosis proteins (inhibits the caspase cascade)
How is IAP upregulated?
by NF-kB, an inflammatory transcription factor
What are the steps in the intrinsic apoptosis pathway?
1) bid binds bax, 2) Bax inserts into membrane, 3) Cyto C + Procaspase 9 escape, 4) Apoptosome forms
What are the extrinsic death signals?
TNF and FAS
How are Procaspase 8’s activated?
cleave each other once in close proximity
What is TRADD?
an adaptor protein that engages TNFr/FAS that has a DED to engage Procaspase 8
What is c-flip?
a protein that binds the DED of TRADD to inhibit Procaspase 8 binding
What are targets of caspases?
DNAse, Lamins, Actin
What does TRAIL stand for?
TNF-related apoptosis-inducing ligand
What is TRAIL?
member of TNF expressed in normal and cancer cells that is bound by TNF-like receptors
Why is TRAIL important in cancer?
can overcome IAP-caspase sequestering, but cancer cells eventually become resistant
What does Caspase stand for?
Cysteine-rich Aspartate Proteases
What apoptosis pathway does cytotoxic chemo activate?
intrinsic
How are the intrinsic/extrinsic pathways changed in cancer?
Bcl-2 is an oncogene; pro-apoptotic (Bax, Bid) often mutated in colorectal tumors; c-flip/IAP overexpressed
What are potential drug targets?
1) c-flip and IAP; 2) rTRAIL or mAb TRAIL-r agonist; 3) Bcl-2 inhibitor (block translation or competitive); 4) upregulate Bid with HDAC inhibitors (vorinostat)
How do the intrinsic and extrinsic pathways communicate?
via Bid, the common link
What are the potential actions for Bid?
1) change Bax for insertion 2) be phosphorylated by ATM to yield cell cycle arrest
What is ATM?
a kinase upregulated in response to DNA damage
