Transcript BCL-2 Family Proteins: Critical Checkpoints of Apoptotic

BCL-2 Family Proteins: Critical Checkpoints of
Apoptotic Cell Death
2010. 3. 31 (Wed)
Nika N. Danial
Clin Cancer Res 2007;13(24) December 15, 2007
Kang Ji-hun
BCL-2 family

BH1,2,3 domain
-a hydrophobic groove (antiapoptotic)
-stabilize by the BH4 domain

Antiapoptotic & proapoptotic proteins
- Antiapoptotic members

- Proapoptotic members
BH4 domain
-require for the function of BCL-2 proteins
-Regulating nuclear factor-KB
: sharing sequence homology within three to four BH domain
 BH3-only protein
- BH: known as BCL-2 homology domain
- subset of proapoptotic molecules
Apoptosis
1.
PCD(programmed cell death)
2.
The two molecular program
- lead to the activation of select member of the caspase
1) Extrinsic pathway
2) Intrinsic pathway
3. BCL-2 family proteins regulate MOMP
- determine the cellular commitment to apoptosis
The Cell, Vol. 504, August 23, 2002, copyright
Intrinsic pathway
1) apoptosome release from mitochondria
2) apoptotic protease : APAF-1, caspase-9, cythchrome c,
mitochondrial electron transport chain
3) release during apoptosis
. Extrinsic pathway
1) operates downstream of death receptors
2) Fas, TNFR(Tumor Necrosis Factor Receptor) family
3) leads to the recruitment of a DISC (death
inducing signaling complex)
Cell Death Regulators
Stress signals from a variety of insults are sensed by
BH3-only proapoptotic proteins
1. MCL-1 : several amino acid between BH3 and BH4 domains
1) posttranslational modification by ubiquitinylation
2) some of close proximity of a GSK-3 phosphorylation site
2. BCL-2 expression
1) specifically blocked the morphologic features of apoptosis
2) required for tumor maintenance
3. BH3-only proapoptotic protein
1) communicate with the multidomain antiapoptotic and proapoptotic
molecules
The intrinsic apoptotic pathway – mitochondria and ER
participate in apoptosis by releasing apoptogenic
factors and Ca2+
BAX & BAK
: gateway to the mitochondrial pathway of apoptosis
1. BAX and BAK fail to release cytochrome c
2. Activation of BAX AND BAK during apoptosis
3. Unlike BAX, BAK monomers are integrated into the MOM
4. Mitochondrial intramembranous homo-oligomerization of BAX & BAK is
a prime candidate mechanism of MOMP and release of cytochrome c
5. Antiapoptotic BCL-2 and BCL-XL block channel formation by BAX
6. BCL-2 family proteins affect Ca2+ dynamics at the ER 7. Ca2+ mobilizing
death stimuli specifically
BH3-only proapoptotic proteins : apoptotic sentinels
upstream of BAX and BAK
1. Indirect activation model
1) antiapoptotic BCL-2, BCL-XL, MCL-1 : to inhibit BAX and BAK
2) these inhibitory interaction seem to be selective
3) two categories of BH domains
① BID, BIM, PUMA
② NOXA, BAD
2. Direct activation model
1) two actegories of BH3 domains; activator , inactivator
2) activator: bind both antiapoptotic and proapoptotic partner
3) inactivator: binding to solely to antiapoptotic partner
4) neutralizaton of all antiapoptotic members by NOXA and BAD
Model for the activation of BAX and BAK downstream of BH3-only proteins
Therapeutic implications
1. Some of the strategies pursued to inhibit the antiapoptotic
BCL-2 family proteins in cancer
2. TW-37 and CHOP : treatment of diffuse large B cell lymphoma
3. GX15-070 : binds to Bcl-2, Bcl-w, Bcl-XL, Mcl-1
4. Molecules, specifically inhibit the production of both BCL-2,
BCL-XL are being considered
Future Directions
1. The discovery of BCL-2
2. Family members mode of action and generation of mimetic
compound
3. Can disrupt their interaction constitute a success story
4. Attests to the power and benefits of basic research in
understanding and targeting cancer
Summary
• The execution of pathway is governed by two
molecular program.
• The two molecular programs are known as the
extrinsic pathway and intrinsic pathway.
• Ultimately lead to the activation of select members of
the caspase family.
• BCL-2 family proteins regulate MOMP and thereby
determine the cellular commitment to apoptosis.
Thank you
for your attention