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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