CST Guide:

c-IAP
TRADD
FADD
Section I: Research Areas
chapter 03: Cell Growth and Death
Regulation of Apoptosis Overview
Inhibition of Apoptosis
TNF, FasL, TRAIL
TNF, FasL, TRAIL
Trophic Factors
TNF-α
TNF-R1
Survival Factors:
Growth Factors,
Cytokines, etc.
Cytoplasm
IKKα
IκBα
TAK1
IKKγ
IκBα
NF-κB
NF-κB
Cytoplasm
Nucleus
IKKβ
Calpain
[Ca 2+ ]
FLIP
XIAP
c-IAP
TRAF2
NIK Casp-8,-10
RIP
TRAF2
Casp-12
Casp-9
ER Stress
RIP1
TRADD
NF-κB
FADD
CYLD
PARP
Itch
FLIP
TRADD
FADD
BID
ROCK
• Cell shrinking
• Membrane
blebbing
DFF40
XIAP
AIF
RIP RAIDD
PIDD
Casp-2
p53
SirT2
HtrA2
Arts
Casp-3,-6,-7
Lamin
A/C
APP
DNA
Fragmentation
RIP
Smac/
Diablo
Endo G
TRAF2
tBID
DFF40
JNK
Cyto c
DFF45
ASK1
Bax
DNA Damage
Bak
Mcl-1
Casp-9
Apaf-1
AIF
PKC
Bcl-2
Bim
ATM/ATR
p53
Puma
Noxa
p90RSK
Puma
Bcl-xL
Noxa
HECTH9
Endo G
Chk1/2
FoxO1
p53
Bad
p53
PI3K
Cell Cycle
Erk1/2
cdc2
14-3-3
Akt
Cellular Stress
FoxO1
JNK
JNK
Bim
c-Jun
NIK
IKKγ CDC37
IKKβ HSP90
IκB
IκB
NF-κB
NF-κB
Cytoplasm
Nucleus
NF-κB
cIAP
TAK1
TAB
IKKα IKKβ
IKKγ
TRAF2
TRADD
HSP90
Casp-8
XIAP
CYLD
HSP70
FADD
HSP90
JNK
HSP27
A20
GSK-3
FoxO1
PTEN
PI3K
PIP 3
Akt
Bcl-2
Casp-3,-6,-7
Bax
HSP27
Apoptosis
Casp-9
Apaf-1 Cyto c HECTH9 HSP70
Akt
FLIP
XIAP
A20
FLIP
BID
Smac/
Diablo
RIP1
HSP70
tBID
HSP27
HSP90
Bax
Bax
Mcl-1
Bak
Bcl-xL
Bim
Bim
PDK1
p70S6K
FAS
Bim
Bad
Bim
PKA
[cAMP]
FoxO1
Ras
Raf
Erk1/2
FoxO1
PKC
p90RSK
Jak
Src
CREB Stat1 Stat3
Bcl-2
Bcl-xL
Cytoplasm
CREB
Stat1
Stat3
HSP90
Apoptosis is a regulated cellular suicide mechanism characterized by nuclear condensation, cell shrinkage, membrane blebbing, and DNA fragmentation. Caspases, a family
of cysteine proteases, are the central regulators of apoptosis. Initiator caspases (including caspase-2, -8, -9, -10, -11, and -12) are closely coupled to pro-apoptotic signals.
Once activated, these caspases cleave and activate downstream effector caspases (including caspase-3, -6, and -7), which in turn execute apoptosis by cleaving cellular
proteins following specific Asp residues. Activation of Fas and TNFR by FasL and TNF, respectively, leads to the activation of caspase-8 and -10. DNA damage induces the
expression of PIDD, which binds to RAIDD and caspase-2 and leads to the activation of caspase-2. Cytochrome c released from damaged mitochondria is coupled to the
activation of caspase-9. XIAP inhibits caspase-3, -7, and -9. Mitochondria release multiple pro-apoptotic molecules, such as Smac/Diablo, AIF, HtrA2, and Endo G, in addition
to cytochrome c. Smac/Diablo binds to XIAP, preventing it from inhibiting caspases. Caspase-11 is induced and activated by pathological pro-inflammatory and pro-apoptotic
stimuli and leads to the activation of caspase-1, thereby promoting inflammatory response and apoptosis by directly processing caspase-3. Caspase-12 and caspase-7 are
activated under ER stress conditions. Anti-apoptotic ligands, including growth factors and cytokines, activate Akt and p90RSK. Akt inhibits Bad by direct phosphorylation and
prevents the expression of Bim by phosphorylating and inhibiting the Forkhead family of transcription factors (FoxO). FoxO promotes apoptosis by upregulating pro-apoptotic
molecules such as FasL and Bim.
Select Reviews:
Degterev, A. and Yuan J. (2008) Nat. Rev. Mol. Cell Biol. 9, 378–390. • Fuchs, Y. and Steller H. (2011) Cell 147, 742–758. • Indran, I.R., Tufo, G., Pervaiz, S., and Brenner
C. (2011) Biochim. Biophys. Acta. 1807, 735–745. • Kaufmann, T., Strasser, A., and Jost, P.J. (2012) Cell Death Differ. 19, 42–50. • Kurokawa, M. and Kornbluth, S.
(2009) Cell 138, 838–854. • Pradelli, L.A., Bénéteau, M., and Ricci, J.E. (2010) Cell. Mol. Life Sci. 67, 1589–1597. • Van Herreweghe, F., Festjens, N., Declercq, W., and
Vandenabeele, P. (2010) Cell. Mol. Life Sci. 67, 1567–1579.
Cell survival requires the active inhibition of apoptosis, which is accomplished by inhibiting the expression of pro-apoptotic factors as well as promoting the expression of
anti-apoptotic factors. The PI3K pathway, activated by many survival factors, leads to the activation of Akt, an important player in survival signaling. PTEN negatively regulates
the PI3K/Akt pathway. Activated Akt phosphorylates and inhibits the pro-apoptotic Bcl-2 family members Bad, Bax, caspase-9, GSK-3, and FoxO1. Many growth factors and
cytokines induce anti-apoptotic Bcl-2 family members. The Jaks and Src phosphorylate and activate Stat3, which in turn induces the expression of Bcl-xL and Bcl-2. Erk1/2
and PKC activate p90RSK, which activates CREB and induces the expression of Bcl-xL and Bcl-2. These Bcl-2 family members protect the integrity of mitochondria, preventing
cytochrome c release and the subsequent activation of caspase-9. TNF-α may activate both pro-apoptotic and anti-apoptotic pathways; TNF-α can induce apoptosis by
activating caspase-8 and -10, but can also inhibit apoptosis via NF-κB, which induces the expression of anti-apoptotic genes such as Bcl-2. cIAP1/2 inhibit TNF-α signaling
by binding to TRAF2. FLIP inhibits the activation of caspase-8.
Select Reviews:
Brumatti, G., Salmanidis, M., and Ekert, P.G. (2010) Cell. Mol. Life Sci. 67, 1619–1630. • Fuchs, Y. and Steller, H. (2011) Cell 147, 742–758. • Fulda, S. and Vucic, D.
(2012) Nat. Rev. Drug Discov. 11, 109–124. • Kaufmann, T., Strasser, A., and Jost, P.J. (2012) Cell Death Differ. 19, 42–50. • Lopez, J. and Meier, P. (2010) Curr. Opin.
Cell Biol. 22, 872–881. • Rong, Y. and Distelhorst, C.W. (2008) Annu. Rev. Physiol. 70, 73–91. • Srinivasula, S.M. and Ashwell, J.D. (2008) Mol. Cell 30, 123–135. •
Zhang, X., Tang, N., Hadden, T.J., and Rishi, A.K. (2011) Biochim. Biophys. Acta. 1813, 1978–1986.
© 2002–2015 Cell Signaling Technology, Inc. • We would like to thank Prof. Junying Yuan, Harvard Medical School, Boston, MA, for reviewing this diagram.
90 For Research Use Only. Not For Use in Diagnostic Procedures. See pages 302 & 303 for Pathway Diagrams, Application, and Reactivity keys.
© 2002–2015 Cell Signaling Technology, Inc. • We would like to thank Prof. Junying Yuan, Harvard Medical School, Boston, MA, for reviewing this diagram.
www.cellsignal.com/cstpathways 91