Apoptosis (Lecture 8 and 9)

Increase C-flip

Anti-apoptotic

Increase BCl-2

Anti-apoptotic, cancer likes

Decrease BAD

Anti-apoptotic

Increase IAPs

Anti-apoptotic

Decrease SMAC/Diablo

Anti-apoptotic

Decrease C-Flip

Increase apoptosis

Decrease BCL2

Increase apoptosis

Increase BAD

Increase apoptosis

Decrease IAPs

Increase Apoptosis

Increase SMAC/DIablo

Increase Apoptosis

Extrinsic Death Receptor Pathway (TNF)

TNF Family:

TNF Receptor, TNF ligand, and Cytotoxic-T-cell permealize cell with granzyme B

TRAIL agonist

Induces Intrinsic Pathway

Trail Receptors

FASR and TNFR

Adaptor Molcules

TRADD and FADD (trimerization induces apoptosis)

What gets activated after procaspase 8?

BID activation

BID

Kiss and run idea

BID kisses BAX in mitochondrial membrane, and activates BAX for normal function

Does BID also kiss and run from BAK

Yes but it’s better with BAX

What inhibits apoptosis in extrinsic death pathway?

C-flip

What molecule doea C-flip bind to and what happens

C-flip binds to FADD and decreases caspase-8, decreases apoptosis, increase in cancer

Procaspase-8 activates what?

Death

FAS receptors include

vesicle/cell display

TNF goes through

TNF trimerization

Increase in MOMP

Increase in apoptosis

BAX and BAK bind together to induce

Death

Once death is induced by BAK and BAX what is released?

Cytochrome C, Procaspase-4, SMAC/Diablo

Circle of death includes

MOMP

APAF 1

Cytochrome-C

Procaspase 9

After an increase in IAPs, what happens?

Decrease in caspase, inhibit of apoptosis, increase in SMAC/Diablo to induce apoptosis

What can bind to BCL2 and BCLXL so BAX and BAK can go through apoptosis?

p53, Venetoclax, BAD, BIM, and PUMA

What does Venetoclax specifically bind to?

BCL2

Which tumor supressor also does the “kiss and run” mechanism?

p53

Nuclear functions of p53

• Decrease prolife (BCL2)

• Increase pro-apoptotic (BAD)

• Increase FASR

• Decrease P13K-AKT-pro life pathway

• Inhibit transcription of FOX03

Cytoplasmic Functions of p53

1. Bind and sequester pro life (BCL2, BCLXL)

2. Delivers BAX and BAK (kiss and run)

3. Stimulate TRAIL with agonist to induce death

BH3 Mimetics

• Venetoclax

• Bind to pro-life proteins so they don’t bind to BAX and BAK

What makes up the apoptosome?

APAF-1 : Cytochrome-C and Procaspase-9