signaling pathways -...
TRANSCRIPT
Signaling pathways
Apoptosis 1. Introduction 2. Extrinsic pathway 3. Intrinsic pathway
Apoptosis
apoptosis autofphagy necrosis
1.
T cell
Viral infection
Death receptors
Cell stress (growth factor depletion, cytoplasmic stress, free radicals), serum starvation
Ionizing radiation
Death receptors
Extrinsic pathway:
- Ligands: cytokines, TNF, Fas ligand - Receptors: cytokine receptors, TNF receptor, Fas receptor
Intrinsic pathway: 1. Withdrawal of survival factors 2. Direct mitochondrial 2. ER stress 3. p53-mediated 4. Viruses
Apoptotic pathways
Survival factor receptors
p53
ER
2.
caspase 3 pro-caspase 3
Cyt c
Apoptotosome
Apaf-1
CAD
I-CAD
CAD
CAD
Intrinsic pathway of apoptosis
Bax & Bak
Radiation: UV, ionizing radiation
Cellular stress: hypoxia
I-CAD
APOPTOSIS
APOPTOSIS
Apaf-1 procaspase 9
Cyt c
3.
BAX: BCL2-associated X protein BAK: BCL2 antagonist/killer CAD: caspase-activated Dnase Cyt c: cytochrome C Apaf-1: apoptotic protease activating factor-1
caspase 9
3b.
Knockout mice
4.
Caspase cascade
The three classes of Bcl-2 proteins
PROTECTORS
KILLERS
REGULATORS
5.
Regulation of apoptosis by Bcl-2 proteins 6.
IAP (inhibitor of apoptosis protein): apoptózis inhibítor
Smac (second mitochondrial activator of apoptosis): az apoptózis második mitokondriális aktivátora
IAP és Smac/DABLO
SMAC/DIABLO
IAP Kaszpáz 3
Cyt C
Kaszpáz 9
APOPTÓZIS
DNS fragmentáció
7.
Roles of IAPs and anti-IAPs in apoptosis 8.
caspase 3 pro-caspase 3
Cyt c
Apoptotosome
Apaf-1 procaspase 9
caspase 9
CAD
I-CAD
CAD
I-CAD
CAD
Intrinsic pathway of apoptosis – the ER stress
Ca++ Ca++
Ca++
Ca++
Ca++ Ca++
Ca++
Ca++
ER stress: misfolded proteins
pro-caspase 12
caspase 12
IP3R Bax & Bak
Ca++
Ca++
Ca++ Ca++
Ca++ Ca++
Ca++
Radiation: UV, ionizing
Cellular stress: hypoxia
DNA damage
APOPTOSIS
APOPTOSIS
Cyt c
9.
ER stress-induced apoptosis 9b.
caspase 8
caspase 3 pro-caspase 3
FASL
FAS
FADD
pro-caspase 8
APOPTOSIS
cytokine
Cytokine receptor
TRADD
FADD
pro-caspase 8
TNF-
TNFR1 receptor
TRADD
FADD
pro-caspase 8
The extrinsic pathway of apoptosis
death domain
INITIATOR CASPASE
EFFECTOR CASPASE
CAD: caspase-activated Dnase I-CAD: inhibitor of CAD
CAD
I-CAD CAD
I-CAD
CAD
Death receptors
APOPTOSIS
10.
DISC
TRADD
FADD
caspase 8
pro-caspase 8
caspase 3 pro-caspase 3
Bid
t-Bid
Cyt c
Apoptotosome
Apaf-1 procaspase 9
caspase 9 caspase 6+7
CAD
I-CAD CAD
I-CAD
CAD
Membrane –bound FASL
FAS
death domain
Death receptor
Bax & Bak
The extrinsic pathway - enhancement
Secreted FASL
APOPTOSIS
APOPTOSIS
11.
Signaling through PI 3-kinase promotes cell survival
Activated PI 3-kinase
PIP2 PIP3
PDK1
PH Domains
Activated receptor Tyrosine kinase
PKB
Active PKB
Dissociation
Activation of PKB by PDK1
Phosphorylation of BAD BAD
Inactive death-inhibitory protein Active death-inhibitory protein
Inactive BAD
14-3-3 protein
Inhibition of apoptosis
mTOR
RTK
12.
Withdraval of survival factor apoptosis
3 ways that survival factors can inhibit apoptosis 13.
M
G1
G2
S
Cell cycle
UUU
E2F
pRB
E2F
pRB
Cyclin E
CDK2
p14
p53 p53
p21
Degradation Apoptosis
Cell cycle arrest
proteasome
Radiation
A key role for p53
MDM2
Cyclin D1
CDK4
P p21
p53
p16
14.
p53
APOPTOSIS
Caspase activation
nucleus
Cytosolic apoptotic pathway
Mitochondrial apoptotic pathway
15.