The signal transduction of unfolded protein response

20 2 2008 4 Chinese Bulletin of Life Sciences Vol. 20, No. 2 Apr., 2008 1004-0374(2008)02-0246-07 (1 201203 2 100049), (unfolded protein response, UPR) Q51;R73.23 A The signal transduction of unfolded protein response LI Ming 1,2, DING Jian 1, MIAO Ze-hong 1 * (1 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; 2 Graduate School of Chinese Academy of Sciences, Beijing 100049, China) Abstract: In the endoplasmic reticulum(er), secretory, transmembrane and ER-resident proteins are folded into their native conformation undergo posttranslational modifications and are finally transformed into their corresponding functional forms. Disruption of protein folding causes ER stress and activates a signaling network called the unfolded proteins response (UPR). UPR increases the biosynthesis capacity of ER chaperones and foldases, and relieves the biosynthetic burden of the secretory pathway by down-regulating expression of genes encoding secreted proteins. Defects in protein folding if not corrected timely, could lead to cell apoptosis. It has been revealed that UPR is highly activated in a variety of tumors types and could contribute to tumor survival and growth. Key words: ER stress; unfold protein response; cancer [1] (unfold protein response UPR) ATP 2007-09-20 2007-12-10 863 (2006AA090304) * E-mail: zhm@jding.dhs.org

247 1 1.1 (ERassociated degradation, ERAD) - [2] (HSP) GRP78 / (CNX/CRT) [3] GRP78 BiP( ) [4] ( ) [5] BiP 78 000 HSP 70 BiP N ATP C BiP BiP DnaJ DnaJ HSP40 5 ERdi1 5 N J BiP BiP ATP C 7 BiP ATP BiP ATP ATP BiP-ATP DnaJ DnaJ- J BiP BiP-ATP DnaJ-BiP-ATP- DnaJ BiP ATP ATP (ADP) DnaJ-Bip- ADP- ADP ATP BiP- [6] BiP BiP PERK IRE1 ATF6 BiP BiP HSP70 HSP90 HSP90 3 N ATP ATP C [7] HSP70 HSP90 ATP HSP70 HSP90 UDP-G (UGGT) UGGT [8] UGGT Asn-Xaa-Ser/Thr Glc3-Man9-GlcNAc2 N- UGGT 1.2 [9] [10] [11] [12] B [13] IRE1/ERN1 PERK/PEK ATF6 PERK IRE1 ATF6

248 1 Bip IRE1 PERK ATF6 PERK elf2 Bip IRE1 TRAF2 ASK JIK JNK c-jun Bcl-2 XBP1 XBP1S ATF6 Bip S1P S2P UPR caspase12 caspase9 caspase3 Ca 2+ Ca 2+ CytoC IRE1 PERK BiP BiP IRE1 PERK BiP IRE1 PERK BiP IRE1 PERK BiP IRE1 PERK IRE1 PERK BiP IRE1 PERK [14] ATF6 BiP IRE1 PERK BiP ATF6 GLS1 GLS2 BiP GLS1 GLS2 BiP GLS2 ATF6 GLS1 BiP ATF6 BiP GLS1 ATF6 [15] PERK I N C 2 α (eif2α) GTP trna eif2-gtp-mettrna i PERK Met eif2α 51 eif2α GDP GTP

249 IRE1 I RNA IRE1α IRE1β IRE1α IRE1β [16] IRE1 BiP IRE1 RNA [17] X-box 1 (XBP1) mrna IRE1 RNA XBP1 mrna, mrna XBP1 BiP [18] ATF6 II ( N C ) 90 000 3 N (bzip) DNA C ATF6 S1P(site-1 protease) S2P(site-2 protease) [15] PERK ATF6 IRE1 1.3 PERK ATF6 IRE1 CHOP CHOP/GADD153 (growth arrest- and DNA damage-inducible gene 153) ATF6 PERK [19] CHOP N C (bzip) CHOP [20] CHOP / [21] CHOP [22] CHOP CHOP GADD34 ERO1 (DR) 5 GADD34 2C eif2α [23] ERO1 [24] DR5 caspases [25] CHOP Bcl-2 CHOP camp (CREB) Bcl-2 [22] IRE1-TRAF2-ASK1-caspase12 IRE1 2(TRAF2) TRAF2 JNK (SAPK) (ASK1) TNF [26] ASK1 [27] TRAF2 caspase12 caspase12 caspase9 caspase3 caspase12 caspase12 [28] Ca 2+ Ca 2+ Bcl-2 Ca 2+ Bax Bak Ca 2+ Ca 2+ Bax Bak [29] Bcl-2 Ca 2+ ( ) Ca 2+ Ca 2+ Ca 2+ [30] 1.4 1/3 [31] - 1(E1) ATP E1 2(E2) E2 3(E3) E3 E2

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