1. 2. Caenorhabditis elegans 3.

: Bcl-2

4. 5. : c/Apaf1 6.

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. ( 16.1). , (blebbing) , , DNA, , .

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. () () DNA (). DNA (). , ( ) (), .

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, . , .

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- (.. ) .

- - -, : 95% - .

. . DNA .

494

2. Caenorhabditis elegans

Caenorhabditis elegans. C. elegans, 1090 131 . , 14 . : ced3 (cell death abnormal) ced4 .. . C. elegans. ced3 ced4 . ced3 Cys, . ced4 ced3. ced9, , , .. , ced3/ced4. ced9 C. elegans. , . , ced9 .

16.3 () C. elegans. : . ced9 , ced3 ced4 . () .

,

-

()

()

495

3.

C. elegans . C. elegans . , , . , , . , . , . , . , . . . .

:

ced3 , ICE. ICE (interleukine converting enzyme: ) 1. 1 15,5 kDa 30kDa ICE. , ICE . : Cys Asp.

, 30-50 kDa () . 3 : (pro-domain) 2- , - (17-12 kDa) - (10-13 kDa). Asp (Asp119, Asp296, Asp316), , . ,

. .

496

16.4

, (Asp119, Asp296, Asp316). - - (pro-domain) ( ) , . , R179, H237 , R341 . Donepudi M and Grutter M, Structure and zymogen activation of caspases, Biophysical Chemistry, 2002, 101-102, 145-153.

16.5 -3. 4 : (p17) (p12). . . Chang H., and Yang X., Proteases for cell suicide: functions and regulation of caspases, Microbiol. Molec. Biol. Reviews 2000, 64, 821-846.

497

. Cys . /.

16.6 . 3, - , Asp. , - - , .

. C- Asp - . . , 13 , 1 13, . ICE 1, 3 CPP32.

498

16.7 C. elegans CED3, . Chang H., and Yang X., Proteases for cell suicide: functions and regulation of caspases, Microbiol. Molec. Biol. Reviews 2000, 64, 821-846. , . , :

ICAD, DNA ( DNA

): DNA DNA.

Bcl-2: .

: ,

(FAK), p21- (PAK) DNA

-ADP- C (RF-C) DNA

499

. . , . , . , , . , : ( 8 9) ( 3, 6 7). . . , . upstream . , .

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500

, , . , . :

: , . .

: . 1-2 % . , . FADD Apaf1/Cyt c, ( , ). - . . 8 DED (death effector domains) 1, 2, 4, 5 9 CARD (caspase recruitment domain). . , , .

Bcl-2

Bcl-2 14 18 . , Bcl-2, , . , Ced9 C. elegans, . Bcl-2 , . , 25 Bcl-2 , . - - Bcl-2. DNA, - Bcl-2. - - Bcl-2 . Bcl-2 B (BH, Bcl-2 homolog), (1 4).

501

16.9 . Bcl-2. Bcl-2 , . Kuwana T., and Newmeyer D., Bcl-2-family proteins and the role of mitochondria in apoptosis, Current Opinion in Cell Biology, 2003, 15, 691-699.

. Bcl-2. Bcl-2 8 -. 1 ( 4-5) , 2 ( 7-8) , 3 ( 2) 4 ( 1) . Petros A., Olejniczak E., Fesik S., Structural biology of the Bcl-2 family of proteins, Biochim. Biophys. Acta, 2004, 1644, 83-94.

Bcl-2 Bcl-2 (Bcl-2, BclX, BclW, A1, Mcl-1) . 1 2. Bcl-2 . Bcl-2 . . Bcl-2, , : Bcl-2 . , , .

. Bcl-2

a.

502

Bcl-2 Bcl-2.

- Bax, Bak Bok, Bcl-2. Bax p53.

- 3, 3. 3 Bad, I3-/Akt.

Bcl-2 . Bcl-2 . . Bcl-2 - , . Bcl-2, .

. . . - . (DD), (DED) (CARD), -.

Fas, FADD (Fas-associated death domain). FADD . . Apaf1 c Apaf1 . Apaf1 Ced4 C. elegans. CARD. CARD Apaf1 ( 1, 2, 4, 5 9). , , c. ATP , Apaf1 c, .

503

. : flip FADD . Bcl-2 Bcl-2 . Bcl-2 . c. , , .. . . .

4.

. TNF (tumor necrosis factor). , 80 (DD: death domain), . . . : Fas (

CD95) 1 (TNFR1), DR3 (TRAMP/Apo3), DR4 (TRAILR1/Apo2), o DR5 (TRAILR2/TRICK2) DR6. , - (DcR1, DcR2, DcR3: Decoy Receptors). , -. . ,

- (DISC: death-inducing signaling complex). - FADD (Fas-associated death domain), TRADD (TNF-receptor-associated death domain), RIP1 (receptor interacting protein kinase 1) DAXX (death associated protein). (DD) DD

504

. DISC.

16.10 , Fas, TNF-R1, DR3, TRAIL-R2 DR6, -

DcR1, DcR2, DcR3. Cys . . , . Curtin J. and Cotter T., Live and let die: regulatory mechanisms in Fas-mediated apoptosis, Cellular Signalling, 2003, 15, 983-992.

Fas

Fas . , - . AICD (activation-induced cell death). Fas. , Fas- . , Fas- , AICD .

Fas Fas . DISC, Fas- .

505

Fas :

Fas . FADD DISC. FADD DD 8. 8 DISC Fas DISC. , 8 , . , 8 Bcl-2, BID, - tBID, c ( ).

16.11 Fas . Fas - FADD (DD) 8 FADD DED ( ). (large clusters), 8 8. BID tBID c . DISC - DAXX, MARKKK, ASK1, JNK . Fas RIP1, RAIDD 2. 2 . Curtin J. and Cotter T., Live and let die: regulatory mechanisms in Fas-mediated apoptosis, Cellular Signalling, 2003, 15, 983-992.

506

TNF . , TNF , MAPK c-Jun. , IB-NFB. IB-NFB c-Jun . , .. , TNF , , .

5. , : c /Apaf1

cl-2, Apaf-1 . c.

, . , c. Bax, Bcl-2. Bcl-2. . , Fas DISC. Fas, FADD 8. 8 Bid, C- (tBid) , Bax, c. tBid c. , c 9 Apaf1 dATP.

- 9, Apaf1 c . ATP Apaf1, ATP/dATP. ATP , , ATP. , 9 , 3, 6 7.

c Bax Bad . , Bad , Akt, ERK ( ), (p21-activated kinase). 14-3-3. 14-3-3 . , Bad Ca2+- 1 ,

507

Bcl-xL. Bcl-xL Bcl-xl-Bax - Bcl-xL.

16.12 . , c . - Bax BH3 Bid c, - Bcl-xL . c Apaf 1, 9 , . , 9 . Desagher S., and Martinou J-C., Mitochondria as the central control point of apoptosis, Trends in Cell Biology, 2000, 10, 369-377

508

16.13 . c Apaf-1, WD-40, . Apaf-1 dATP/ATP. Apaf-1, CARD, --9. --9, -9, CARD Apaf-1. XIAP -9 . -9, SMAC, . -9 , . Cain K., Bratton SB., Cohen GM, The Apaf-1 apoptosome : a large caspace-activating complex, Biochimie 84 (2002) 203-214.

509

16.13 . 9.

, . . : 9 Apaf 1. Fuentes-Prior P., and Salvesen G., Biochem. J., 2004, 384, 201-232

. . , Apaf-1 d. paf-1 WD40, CED-4 CARD. [1] , c, Apaf-1. dATP dADP Apaf-1. [2] , Apaf-1 , . [3] -9, -9 , . -9 , 3.

9

Apaf1

510

6.

, , . , . , -, , DNA. , .

I3 I3- , . 3 Akt, PtdInsP3 I3-. Bad Akt. Bad Bcl-2. Akt , , . 14-3-3 , Bad .

16.14 PI3-/Akt . PI3-/Akt Bad, Bcl-2 . PI3 Bad Akt. Bad . Bad Akt Bad 14-3-3. Bad .

511

p53

p53 DNA . , p53 RNA . p53 bax. Bax Bcl-2 . Bax p53 c . c , Apaf1, 8 . Trans- p53 p53, Bax , . , Fas p53. , .

16.15 DNA p53 . DNA ATM p53. , p53 bax. Bax c . p53 , .

512

Abraham M., and Shaham S., Death without caspases, caspases without death, Trends in Cell Biology, 2004, 14, 184-193

Cain K., Bratton S., Cohen G, The Apaf-1 apoptosoma: a large caspase-activating complex, Biochinie, 2002, 84, 203-214

Chang H., and Yang X., Proteases for cell suicide: functions and regulation of caspases, Microbiol. Molec. Biol. Reviews 2000, 64, 821-846

Curtin J. and Cotter T., Live and let die: regulatory mechanisms in Fas-mediated apoptosis, Cellular Signalling, 2003, 15, 983-992

Desagher S., and Martinou J-C., Mitochondria as the central control point of apoptosis, Trends in Cell Biology, 2000, 10, 369-377

Donepudi M and Grtter M, Structure and zymogen activation of caspases, Biophysical Chemistry, 2002, 101-102, 145-153

Fuentes-Prior P., and Salvesen G., The protein structures that shape caspase activity, specificity, activation and inhibition, Biochem. J., 2004, 384, 201-232

Green D., and Kroemer G., The central executioners of apoptosis: caspases or mitochondria? Trends in Cell Biology, 1998, 8, 267-271

Grtter M, Caspases: key players in programmed cell death, Current Opinion in Structural Biology, 2000, 10, 649-655

Krauss G., Biochemistry of Signal transduction and Regulation, Chapter 15: Apoptosis, Wiley Editions, 2002

Kuwana T., and Newmeyer D., Bcl-2-family proteins and the role of mitochondria in apoptosis, Current Opinion in Cell Biology, 2003, 15, 691-699.

Petros A., Olejniczak E., Fesik S., Structural biology of the Bcl-2 family of proteins, Biochim. Biophys. Acta, 2004, 1644, 83-94.

Song Z., and Steller H., Death by desing: mechanism and control of apoptosis, Trends in Cell Biology, 1999, 9, M49-52

Zhivotovsky B., and Orrenius S., Caspase-2 function in response to DNA damage, Biochem Biophys. Res. Commun., 2005, 331, 859-867