摘要
在大鼠和沙土鼠动物全脑缺血模型中,短暂的全脑缺血导致海马CA1区锥体神经元的选择性死亡,这种迟发的神经元细胞丢失只有在缺血/复灌2—4天后才能观察到。实验证据表明,这种迟发的神经元死亡的分子机制中存在凋亡过程。JNK蛋白激酶信号的激活是介导脑缺血应激引起神经细胞凋亡的重要通路;最近,一种胞内丝/苏氨酸蛋白激酶MLK3被发现,MLK3作为JNK级联上游的重要活化因子,通过直接磷酸化并激活中游MKK4/7蛋白激酶,从而激活JNK应激信号通路。MLK3介导了JNK诱导的神经元凋亡和脑缺血损伤通路,并因此受到重视。然而,关于脑缺血/复灌激活MLK3的信号调控分子机制尚不清楚。本文主要探讨了MLK3的两种直接结合蛋白POSH和Rac1对MLK3/JNK信号通路以及对脑缺血损伤的调控作用。
1.POSH通过组装POSH-MLK3/MKK4/JNKs信号模块介导JNK通路的激活和脑缺血/复灌诱导的海马CA1区神经元损伤
我们首先用免疫印迹和免疫组化的方法观察了海马CA1区POSH蛋白在SD大鼠脑缺血/复灌后的表达分布情况。结果显示,假手术组和缺血/复灌组POSH蛋白的胞浆免疫活性在海马CA1和CA3锥体细胞较强,然而在DG颗粒细胞表达较弱。免疫共沉淀实验表明,POSH能与MLK3、MKK4以及p-JNKs免疫共结合,在复灌30分钟时达最高值,在复灌1-3天时仍高于对照组。同时,在脑缺血/复灌30分钟和3天时MLK3/MKK4/JNKs信号通路存在两个活化峰。脑室注射POSH反义寡核苷酸不仅能显著降低其蛋白表达、抑制POSH与MLK3,MKK4,和p-JNKs级联组分的结合,还能够抑制MLK3/MKK4/JNKs信号通路的激活。而且,脑室注射POSH反义寡核苷酸显著增加了脑缺血/复灌5天后海马CA1区存活神经元的数量。结果提示,POSH可能作为支架蛋白介导了脑缺血/复灌后海马CA1区JNK信号通路的激活,POSH反义寡核菅酸通过抑制MLK3/MKK4/JNKs通路,并涉及c-Jun和Caspase-3的抑制,发挥对脑缺血损伤的保护作用。
Transient, severe global ischemia in rats and gerbils leads to selective and delayed neuronal death of pyramidal neurons in the hippocampal CA1, which is not detected until 2-4 d after induction of ischemia. Several lines of evidence have been proposed to suggest that apoptotic process underlies the molecular mechanism of this delayed neuronal cell death. Considerable evidence suggests that c-Jun NH2-terminal kinase (JNK) is an important kinase mediating the neuronal cell death in response to cerebral ischemia. Recently, an intracellular serine/threonine kinase, mixed-lineage kinase 3 (MLK3) has been identified as a novel upstream activator of the JNK pathway. MLK3 functions as a MAPK kinase kinase (MAPKKK) of the JNK stress pathway by directly phosphorylating and activating the JNK activators SEK1/MKK4 and MKK7. MLK3 has garnered attention as an important mediator of JNK-mediated neuronal apoptosis and ischemic injury. However, the molecular mechanisms that regulate MLK3 activity in cerebral ischemic-reperfusion has not been extensively delineated. The overall goal of the present study is to understand the molecular basis by which MLK3 and its signaling pathways are negatively regulated by targeting MLK3 interacting proteins in cerebral ischemia.
1. POSH is an important mediator of JNK pathway activation and ischemic injury by compositing the POSH/MKK4/JNK signaling complex in vulnerable CA1 region following transient global ischemia.
We investigated the expression and subcellular localization of the multidomain protein POSH (plenty of SH3s) by immunohistochemistry and Western blot analysis in rat hippocampal CA1 region following cerebral ischemia. Our results indicated that the cytosol immunoreactivity of POSH was strong in CA1-CA3 pyramidal cell but weak in DG granule cell of rat hippocampus both in sham control and after reperfusion. Coimmunoprecipitation experiments showed that the interactions of MLK3, MKK4 and phospho-JNKs with POSH were persistently enhanced during the early (30 min) and the later reperfusion period (from 1 d to 3 d) compared with sham
引文
Allsopp TE, Wyatt S, Paterson HF, Davies AM. (1993) The proto-oncogene bcl-2 can selectively rescue neurotrophic factor-dependent neurons from apoptosis. Cell 73:295-307
Barr RK, Kendrick TS, Bogoyevitch MA. (2002) Identification of the critical features of a small peptide inhibitor of JNK activity. J Biol Chem 277:10987-10997
Bazenet CE, Mota MA, Rubin LL. (1998) The small GTP-binding protein Cdc42 is required for nerve growth factor withdrawal-induced neuronal death. Proc Natl Acad Sci USA 95:3984-3989
Bennett BL, Sasaki DT, Murray BW, O'Leary EC, Sakata ST, Xu W, Leisten JC, Motiwala A, Pierce S, Satoh Y, Bhagwat SS, Manning AM, Anderson DW. (2001) SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase. Proc Natl Acad Sci USA 98:13681-13686
Berg MM, Sternberg DW, Parada LF, Chao MV. (1992) K-252a inhibits nerve growth factor-induced trk proto-oncogene tyrosine phosphorylation and kinase activity. J Biol Chem 267:13-16
Bock BC, Vacratsis PO, Qamirani E, Gallo KA. (2000) Cdc42-induced activation of the mixed-lineage kinase SPRK in vivo. Requirement of the Cdc42/Rac interactive binding motif and changes in phosphorylation. J Biol Chem 275:14231-14241
Borsello T, Clarke PG, Hirt L, Vercelli A, Repici M, Schorderet DF, Bogousslavsky J, Bonny C. (2003) A peptide inhibitor of c-Jun N-terminal kinase protects against excitotoxicity and cerebral ischemia. Nat Med 9:1180-1186
Breitschopf K, Haendeler J, Malchow P, Zeiher AM, Dimmeler S. (2000) Posttranslational modification of Bcl-2 facilitates its proteasome-dependent degradation: molecular characterization of the involved signaling pathway. Mol Cell Biol 20:1886-1896
Carboni S, Hiver A, Szyndralewiez C, Gaillard P, Gotteland JP, Vitte PA. (2004) AS601245 (1,3-benzothiazol-2-yl (2-[[2-(3-pyridinyl) ethyl] amino]-4 pyrimidinyl) acetonitrile): a c-Jun NH2-terminal protein kinase inhibitor with neuroprotective properties. J Pharmacol Exp Ther 310:25-32
Chuang TH, Hahn KM, Lee JD, Danley DE, Bokoch GM. (1997) The small GTPase Cdc42 initiates an apoptotic signaling pathway in Jurkat T lymphocytes. Mol Biol Cell 8:1687-1698
Davis RJ. (2000) Signal transduction by the JNK group of MAP kinases. Cell 103:239-252
Deng X, Ruvolo P, Carr B, May WS, Jr. (2000) Survival function of ERK1/2 as IL-3-activated, staurosporine-resistant Bcl2 kinases. Proc Natl Acad Sci USA 97:1578-1583
Donovan N, Becker EB, Konishi Y, Bonni A. (2002) JNK phosphorylation and activation of BAD couples the stress-activated signaling pathway to the cell death machinery. J Biol Chem 277:40944-40949
Figueroa C, Tarras S, Taylor J, Vojtek AB. (2003) Akt2 negatively regulates assembly of the POSH-MLK-JNK signaling complex. J Biol Chem 278:47922-47927
Foltz IN, Gerl RE, Wieler JS, Luckach M, Salmon RA, Schrader JW. (1998) Human mitogen-activated protein kinase kinase 7 (MKK7) is a highly conserved c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) activated by environmental stresses and physiological stimuli. J Biol Chem 273:9344-9351
Gallo KA, Johnson GL. (2002) Mixed-lineage kinase control of JNK and p38 MAPK pathways. Nat Rev Mol Cell Biol 3:663-672
Gallo KA, Mark MR, Scadden DT, Wang Z, Gu Q, Godowski PJ. (1994) Identification and characterization of SPRK, a novel src-homology 3 domain-containing proline-rich kinase with serine/threonine kinase activity. J Biol Chem 269:15092-15100
Gao Y, Signore AP, Yin W, Cao G, Yin XM, Sun F, Luo Y, Graham SH, Chen J. (2005) Neuroprotection against focal ischemic brain injury by inhibition of c-Jun N-terminal kinase and attenuation of the mitochondrial apoptosis-signaling pathway. J Cereb Blood Flow Metab 25:694-712
Guan QH, Pei DS, Zhang QG, Hao ZB, Xu TL, Zhang GY. (2005) The neuroprotective action of SP600125, a new inhibitor of JNK, on transient brain ischemia/reperfusion-induced neuronal death in rat hippocampal CA1 via nuclear and non-nuclear pathways. Brain Res 1035:51-59
Han Z, Boyle DL, Chang L, Bennett B, Karin M, Yang L, Manning AM, Firestein GS. (2001) c-Jun N-terminal kinase is required for metalloproteinase expression and joint destruction in inflammatory arthritis. J Clin Invest 108:73-81
Harding TC, Xue L, Bienemann A, Haywood D, Dickens M, Tolkovsky AM, Uney JB. (2001) Inhibition of JNK by overexpression of the JNL binding domain of JIP-1 prevents apoptosis in sympathetic neurons. J Biol Chem 276:4531 -4534
Harris CA, Deshmukh M, Tsui-Pierchala B, Maroney AC, Johnson EM, Jr. (2002) Inhibition of the c-Jun N-terminal kinase signaling pathway by the mixed lineage kinase inhibitor CEP-1347 (KT7515) preserves metabolism and growth of trophic factor-deprived neurons. J Neurosci 22:103-113
Hatai T, Matsuzawa A, Inoshita S, Mochida Y, Kuroda T, Sakamaki K, Kuida K, Yonehara S, Ichijo H, Takeda K. (2000) Execution of apoptosis signal-regulating kinase 1 (ASK1)-induced apoptosis by the mitochondria-dependent Caspase activation. J Biol Chem 275:26576-26581
Herdegen T, Claret FX, Kallunki T, Martin-Villalba A, Winter C. Hunter T, Karin M. (1998) Lasting N-terminal phosphorylation of c-Jun and activation of c-Jun N-terminal kinases after neuronal injury. J Neurosci 18:5124-5135
Hirt L, Badaut J, Thevenet J, Granziera C, Regli L, Maurer F, Bonny C, Bogousslavsky J. (2004) D-JNKI1, a cell-penetrating c-Jun-N-terminal kinase inhibitor, protects against cell death in severe cerebral ischemia. Stroke 35:1738-1743
Hockenbery DM, Oltvai ZN, Yin XM, Milliman CL, Korsmeyer SJ. (1993) Bcl-2 functions in an antioxidant pathway to prevent apoptosis. Cell 75:241-251
Ichijo H, Nishida E, Irie K, ten Dijke P, Saitoh M, Moriguchi T, Takagi M, Matsumoto K, Miyazono K, Gotoh Y. (1997) Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways. Science 275:90-94
Ikeda A, Masaki M, Kozutsumi Y, Oka S, Kawasaki T. (2001) Identification and characterization of functional domains in a mixed lineage kinase LZK. FEBS Lett 488:190-195
Kaneko M, Saito Y, Saito H, Matsumoto T, Matsuda Y, Vaught JL, Dionne CA, Angeles TS, Glicksman MA, Neff NT, Rotella DP, Kauer JC, Mallamo JP, Hudkins RL, Murakata C. (1997) Neurotrophic 3,9-bis[(alkylthio)methyl]-and-bis(alkoxymethyl)-K-252a derivatives. J Med Chem 40:1863-1869
Katayama T, Imaizumi K, Sato N, Miyoshi K, Kudo T, Hitomi J, Morihara T, Yoneda T, Gomi F, Mori Y, Nakano Y, Takeda J, Tsuda T, Itoyama Y, Murayama O, Takashima A, St George-Hyslop P, Takeda M, Tohyama M. (1999) Presenilin-1 mutations downregulate the signalling pathway of the unfolded-protein response. Nat Cell Biol 1:479-485
Kennedy LM. (1975) Address by L. M. Kennedy, D.D.S. Va Dent J 52:10-17
Kuan CY, Yang DD, Samanta Roy DR, Davis RJ, Rakic P, Flavell RA. (1999) The Jnk1 and Jnk2 protein kinases are required for regional specific apoptosis during early brain development. Neuron 22:667-676
Kuwabara M, Takahashi K, Inanami O. (2003) Induction of apoptosis through the activation of SAPK/JNK followed by the expression of death receptor Fas in X-irradiated cells. J Radiat Res (Tokyo) 44:203-209
Kyriakis JM, Avruch J. (2001) Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. Physiol Rev 81:807-869
Lawler S, Fleming Y, Goedert M, Cohen P. (1998) Synergistic activation of SAPK1/JNK1 by two MAP kinase kinases in vitro. Curr Biol 8:1387-1390
Lee CM, Onesime D, Reddy CD, Dhanasekaran N, Reddy EP. (2002) JLP: A scaffolding protein that tethers JNK/p38MAPK signaling modules and transcription factors. Proc Natl Acad Sci U S A 99:14189-14194
Lei K, Davis RJ. (2003) JNK phosphorylation of Bim-related members of the Bcl2 family induces Bax-dependent apoptosis. Proc Natl Acad Sci U S A 100:2432-2437
Lei K, Nimnual A, Zong WX, Kennedy NJ, Flavell RA, Thompson CB, Bar-Sagi D, Davis RJ. (2002) The Bax subfamily of Bcl2-related proteins is essential for apoptotic signal transduction by c-Jun NH(2)-terminal kinase. Mol Cell Biol 22:4929-4942
Leung IW, Lassam N. (1998) Dimerization via tandem leucine zippers is essential for the activation of the mitogen-activated protein kinase kinase kinase, MLK-3. J Biol Chem 273:32408-32415
Leung IW, Lassam N. (2001) The kinase activation loop is the key to mixed lineage kinase-3 activation via both autophosphorylation and hematopoietic progenitor kinase 1 phosphorylation. J Biol Chem 276:1961-1967
Liu H, Nishitoh H, Ichijo H, Kyriakis JM. (2000a) Activation of apoptosis signal-regulating kinase 1 (ASK1) by tumor necrosis factor receptor-associated factor 2 requires prior dissociation of the ASK1 inhibitor thioredoxin. Mol Cell Biol 20:2198-2208
Liu TC, Huang CJ, Chu YC, Wei CC, Chou CC, Chou MY, Chou CK, Yang JJ. (2000b) Cloning and expression of ZAK, a mixed lineage kinase-like protein containing a leucine-zipper and a sterile-alpha motif. Biochem Biophys Res Commun 274:811-816
Maroney AC, Finn JP, Bozyczko-Coyne D, O'Kane TM, Neff NT, Tolkovsky AM, Park DS, Yan CY, Troy CM, Greene LA. (1999) CEP-1347 (KT7515), an inhibitor of JNK activation, rescues sympathetic neurons and neuronally differentiated PC12 cells from death evoked by three distinct insults. J Neurochem 73:1901-1912
Maroney AC, Finn JP, Connors TJ, Durkin JT, Angeles T, Gessner G, Xu Z, Meyer SL, Savage MJ, Greene LA, Scott RW, Vaught JL. (2001) Cep-1347 (KT7515), a semisynthetic inhibitor of the mixed lineage kinase family. J Biol Chem 276:25302-25308
Maroney AC, Glicksman MA, Basma AN, Walton KM, Knight E, Jr., Murphy CA, Bartlett BA, Finn JP, Angeles T, Matsuda Y, Neff NT, Dionne CA. (1998) Motoneuron apoptosis is blocked by CEP-1347 (KT 7515), a novel inhibitor of the JNK signaling pathway. J Neurosci 18:104-111
Matsuzawa A, Ichijo H. (2001) Molecular mechanisms of the decision between life and death: regulation of apoptosis by apoptosis signal-regulating kinase 1. J Biochem (Tokyo) 130:1-8
Maundrell K, Antonsson B, Magnenat E, Camps M, Muda M, Chabert C, Gillieron C, Boschert U, Vial-Knecht E, Martinou JC, Arkinstall S. (1997) Bcl-2 undergoes phosphorylation by c-Jun N-terminal kinase/stress-activated protein kinases in the presence of the constitutively active GTP-binding protein Racl. J Biol Chem 272:25238-25242
McDonald PH, Chow CW, Miller WE, Laporte SA, Field ME, Lin FT, Davis RJ, Lefkowitz RJ. (2000) Beta-arrestin 2: a receptor-regulated MAPK scaffold for the activation of JNK3. Science 290:1574-1577
Merritt SE, Mata M, Nihalani D, Zhu C, Hu X, Holzman LB. (1999) The mixed lineage kinase DLK utilizes MKK7 and not MKK4 as substrate. J Biol Chem 274:10195-10202
Mielke K, Herdegen T. (2000) JNK and p38 stresskinases-degenerative effectors of signal-transduction-cascades in the nervous system. Prog Neurobiol 61:45-60
Mota M, Reeder M, Chernoff J, Bazenet CE. (2001) Evidence for a role of mixed lineage kinases in neuronal apoptosis. J Neurosci 21:4949-4957
Murakata C, Kaneko M, Gessner G, Angeles TS, Ator MA, O'Kane TM, McKenna BA, Thomas BA, Mathiasen JR, Saporito MS, Bozyczko-Coyne D, Hudkins RL. (2002) Mixed lineage kinase activity of indolocarbazole analogues. Bioorg Med Chem Lett 12:147-150
Nicotra A, Parvez S. (2002) Apoptotic molecules and MPTP-induced cell death. Neurotoxicol Teratol 24:599-605
Nihalani D, Merritt S, Holzman LB. (2000) Identification of structural and functional domains in mixed lineage kinase dual leucine zipper-bearing kinase required for complex formation and stress-activated protein kinase activation. J Biol Chem 275:7273-7279
Nishina H, Nakagawa K, Azuma N, Katada T. (2003) Activation mechanism and physiological roles of stress-activated protein kinase/c-Jun NH2-terminal kinase in mammalian cells. J Biol Regul Homeost Agents 17:295-302
Niwa M, Sidrauski C, Kaufman RJ, Walter P. (1999) A role for presenilin-1 in nuclear accumulation of Irel fragments and induction of the mammalian unfolded protein response. Cell 99:691-702
Oltvai ZN, Milliman CL, Korsmeyer SJ. (1993) Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell 74:609-619
Pan G, O'Rourke K, Dixit VM. (1998) Caspase-9, Bcl-XL, and Apaf-1 form a ternary complex. J Biol Chem 273:5841-5845
Pan J, Zhang QG, Zhang GY. (2005) The neuroprotective effects of K252a through inhibiting MLK3/MKK7/JNK3 signaling pathway on ischemic brain injury in rat hippocampal CA1 region. Neuroscience 13 1:147-159
Phelan DR, Price G, Liu YF, Dorow DS. (2001) Activated JNK phosphorylates the c-terminal domain of MLK2 that is required for MLK2-induced apoptosis. J Biol Chem 276:10801 -10810
Roux PP, Dorval G, Boudreau M, Angers-Loustau A, Morris SJ, Makkerh J, Barker PA. (2002) K252a and CEP1347 are neuroprotective compounds that inhibit mixed-lineage kinase-3 and induce activation of Akt and ERK. J Biol Chem 277:49473-49480
Saporito MS, Hudkins RL, Maroney AC. (2002) Discovery of CEP-1347/KT-7515, an inhibitor of the JNK/SAPK pathway for the treatment of neurodegenerative diseases. Prog Med Chem 40:23-62
Song JJ, Lee YJ. (2005) Dissociation of Akt1 from its negative regulator JIP1 is mediated through the ASK1-MEK-JNK signal transduction pathway during metabolic oxidative stress: a negative feedback loop. J Cell Biol 170:61-72
Tapon N, Nagata K, Lamarche N, Hall A. (1998) A new rac target POSH is an SH3-containing scaffold protein involved in the JNK and NF-kappaB signalling pathways. Embo J 17:1395-1404
Teramoto H, Coso OA, Miyata H, Igishi T, Miki T, Gutkind JS. (1996) Signaling from the small GTP-binding proteins Rac1 and Cdc42 to the c-Jun N-terminal kinase/stress-activated protein kinase pathway. A role for mixed lineage kinase 3/protein-tyrosine kinase 1, a novel member of the mixed lineage kinase family. J Biol Chem 271:27225-27228
Tibbies LA, Ing YL, Kiefer F, Chan J, Iscove N, Woodgett JR, Lassam NJ. (1996) MLK-3 activates the SAPK/JNK and p38/RK pathways via SEK1 and MKK3/6. EmboJ 15:7026-7035
Tibbies LA, Woodgett JR. (1999) The stress-activated protein kinase pathways. Cell Mol Life Sci 55:1230-1254
Tobiume K, Matsuzawa A, Takahashi T, Nishitoh H, Morita K, Takeda K, Minowa O, Miyazono K, Noda T, Ichijo H. (2001) ASK1 is required for sustained activations of JNK/p38 MAP kinases and apoptosis. EMBO Rep 2:222-228
Tournier C, Hess P, Yang DD, Xu J, Turner TK, Nimnual A, Bar-Sagi D, Jones SN, Flavell RA, Davis RJ. (2000) Requirement of JNK for stress-induced activation of the cytochrome c-mediated death pathway. Science 288:870-874
Wang J, Van De Water TR, Bonny C, de Ribaupierre F, Puel JL, Zine A. (2003) A peptide inhibitor of c-Jun N-terminal kinase protects against both aminoglycoside and acoustic trauma-induced auditory hair cell death and hearing loss. J Neurosci 23:8596-8607
Wang W, Shi L, Xie Y, Ma C, Li W, Su X, Huang S, Chen R, Zhu Z, Mao Z, Han Y, Li M. (2004) SP600125, a new JNK inhibitor, protects dopaminergic neurons in the MPTP model of Parkinson's disease. Neurosci Res 48:195-202
Weston CR, Davis RJ. (2002) The INK signal transduction pathway. Curr Opin Genet Dev 12:14-21
Xia Z, Dickens M, Raingeaud J, Davis RJ, Greenberg ME. (1995) Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Science 270:1326-1331
Xu Z, Kukekov NV, Greene LA. (2003) POSH acts as a scaffold for a multiprotein complex that mediates JNK activation in apoptosis. Embo J22:252-261
Xu Z, Maroney AC, Dobrzanski P, Kukekov NV, Greene LA. (2001) The MLK family mediates c-Jun N-terminal kinase activation in neuronal apoptosis. Mol Cell Biol 21:4713-4724
Yamaguchi K, Shirakabe K, Shibuya H, Irie K., Oishi I, Ueno N, Taniguchi T, Nishida E, Matsumoto K. (1995) Identification of a member of the MAPKKK family as a potential mediator of TGF-beta signal transduction. Science 270:2008-2011
Yamamoto K, Ichijo H, Korsmeyer SJ. (1999) Bcl-2 is phosphorylated and inactivated by an ASK1/Jun N-terminal protein kinase pathway normally activated at G(2)/M. Mol Cell Biol 19:8469-8478
Yamauchi J, Kaziro Y, Itoh H. (1999) Differential regulation of mitogen-activated protein kinase kinase 4 (MKK4) and 7 (MKK7) by signaling from G protein beta gamma subunit in human embryonal kidney 293 cells. J Biol Chem 274:1957-1965
Yang DD, Kuan CY, Whitmarsh AJ, Rincon M, Zheng TS, Davis RJ, Rakic P, Flavell RA. (1997) Absence of excitotoxicity-induced apoptosis in the hippocampus of mice lacking the Jnk3 gene. Nature 389:865-870
Yang E, Zha J, Jockel J, Boise LH, Thompson CB, Korsmeyer SJ. (1995) Bad, a heterodimeric partner for Bcl-ⅩL and Bcl-2, displaces Bax and promotes cell death. Cell 80:285-291
Yasuda J, Whitmarsh A J, Cavanagh J, Sharma M, Davis RJ. (1999) The JIP group ofmitogen-activated protein kinase scaffold proteins. Mol Cell Biol 19:7245-7254
Zhang H, Wu W, Du Y, Santos S J, Conrad SE, Watson JT, Grammatikakis N, Gallo KA. (2004) Hsp90/p50cdc37 is required for mixed-lineage kinase (MLK) 3 signaling. J Biol Chem 279:19457-19463
Zhang L, Chert J, Fu H. (1999) Suppression of apoptosis signal-regulating kinase 1-induced cell death by 14-3-3 proteins. Proc Natl Acad Sci U S A 96:8511-8515
Zhu X, Ogawa O, Wang Y, Perry G, Smith MA. (2003) JKK1, an upstream activator of JNK/SAPK, is activated in Alzheimer's disease. J Neurochem 85:87-93
Brichese L, Cazettes G, Valette A. (2004) JNK is associated with Bcl-2 and PP1 in mitochondria: paclitaxel induces its activation and its association with the phosphorylated form of Bcl-2. Cell Cycle 3:1312-1319
Carboni S, Antonsson B, Gaillard P, Gotteland JP, Gillon JY, Vitte PA. (2005) Control of death receptor and mitochondrial-dependent apoptosis by c-Jun N-terminal kinase in hippocampal CA1 neurones following global transient ischaemia. J Neurochem 92:1054-1060
Davis RJ. (2000) Signal transduction by the JNK group of MAP kinases. Cell 103:239-252
Gallo KA, Johnson GL. (2002) Mixed-lineage kinase control of JNK and p38 MAPK pathways. Nat Rev Mol Cell Biol 3:663-672
Gao Y, Signore AP, Yin W, Cao G, Yin XM, Sun F, Luo Y, Graham SH, Chen J. (2005) Neuroprotection against focal ischemic brain injury by inhibition of c-Jun N-terminal kinase and attenuation of the mitochondrial apoptosis-signaling pathway. J Cereb Blood Flow Metab 25:694-712
Gu Z, Jiang Q, Zhang G. (2001) c-Jun N-terminal kinase activation in hippocampal CA1 region was involved in ischemic injury. Neuroreport 12:897-900
Gu Z, Jiang Q, Zhang G, Cui Z, Zhu Z. (2000) Diphosphorylation of extracellular signal-regulated kinases and c-Jun N-terminal protein kinases in brain ischemic tolerance in rat. Brain Res 860:157-160
Ham J, Eilers A, Whitfield J, Neame SJ, Shah B. (2000) c-Jun and the transcriptional control of neuronal apoptosis. Biochem Pharmacol 60:1015-1021
Herdegen T, Claret FX, Kallunki T, Martin-Villalba A, Winter C, Hunter T, Karin M. (1998) Lasting N-terminal phosphorylation of c-Jun and activation of c-Jun N-terminal kinases after neuronal injury. J Neurosci 18:5124-5135
Irving EA, Bamford M. (2002) Role of mitogen- and stress-activated kinases in ischemic injury. J Cereb Blood Flow Metab 22:631 -647
Kennedy LM. (1975) Address by L. M. Kennedy, D.D.S. Va Dent J 52:10-17
Kuan CY, Whitmarsh AJ, Yang DD, Liao G, Schloemer AJ, Dong C, Bao J, Banasiak KJ, Haddad GG, Flavell RA, Davis RJ, Rakic P. (2003) A critical role of neural-specific JNK3 for ischemic apoptosis. Proc Natl Acad Sci U S A 100:15184-15189
Lei K, Nimnual A, Zong WX, Kennedy NJ, Flavell RA, Thompson CB, Bar-Sagi D, Davis RJ. (2002) The Bax subfamily of Bcl2-related proteins is essential for apoptotic signal transduction by c-Jun NH(2)-terminal kinase. Mol Cell Biol 22:4929-4942
Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265-275
Matsuoka Y, Okazaki M, Zhao H, Asai S, Ishikawa K, Kitamura Y. (1999) Phosphorylation of c-Jun and its localization with heme oxygenase-1 and cyclooxygenase-2 in CA1 pyramidal neurons after transient forebrain ischemia. J Cereb Blood Flow Metab 19:1247-1255
Matsuzawa A, Ichijo H. (2001) Molecular mechanisms of the decision between life and death: regulation of apoptosis by apoptosis signal-regulating kinase 1.J Biochem (Tokyo) 130:1-8
Ogita K, Yoneda Y. (1994) Selective potentiation of DNA binding activities of both activator protein 1 and cyclic AMP response element binding protein through in vivo activation of N-methyl-D-aspartate receptor complex in mouse brain. J Neurochem 63:525-534
Okuno S, Saito A, Hayashi T, Chan PH. (2004) The c-Jun N-terminal protein kinase signaling pathway mediates Bax activation and subsequent neuronal apoptosis through interaction with Bim after transient focal cerebral ischemia. J Neurosci 24:7879-7887
Pulsinelli WA, Brierley JB. (1979) A new model of bilateral hemispheric ischemia in the unanesthetized rat. Stroke 10:267-272
Putcha GV, Le S, Frank S, Besirli CG, Clark K, Chu B, Alix S, Youle RJ, LaMarche A, Maroney AC, Johnson EM, Jr. (2003) JNK-mediated BIM phosphorylation potentiates BAX-dependent apoptosis. Neuron 38:899-914
Sunayama J, Tsuruta F, Masuyama N, Gotoh Y. (2005) JNK antagonizes Akt-mediated survival signals by phosphorylating 14-3-3. J Cell Biol 170:295-304
Xu Z, Kukekov NV, Greene LA. (2003) POSH acts as a scaffold for a multiprotein complex that mediates JNK activation in apoptosis. Embo J 22:252-261
Zhang C, Shen W, Zhang G. (2002) N-methyl-D-aspartate receptor and L-type voltage-gated Ca(2+) channel antagonists suppress the release of cytochrome c and the expression of proCaspase-3 in rat hippocampus after global brain ischemia. Neurosci Lett 328:265-268
Alessi DR, Andjelkovic M, Caudwell B, Cron P, Morrice N. Cohen P, Hemmings BA. (1996) Mechanism of activation of protein kinase B by insulin and IGF-1. Embo J 15:6541-6551
Alessi DR, Cohen P. (1998) Mechanism of activation and function of protein kinase B. Curr Opin Genet Dev 8:55-62
Alloatti G, Montrucchio G, Lembo G, Hirsch E. (2004) Phosphoinositide 3-kinase gamma: kinase-dependent and -independent activities in cardiovascular function and disease. Biochem Soc Trans 32:383-386
Barthwal MK, Sathyanarayana P, Kundu CN, Rana B, Pradeep A, Sharma C, Woodgett JR, Rana A. (2003) Negative regulation of mixed lineage kinase 3 by protein kinase B/AKT leads to cell survival. J Biol Chem 278:3897-3902
Bazenet CE, Mota MA, Rubin LL. (1998) The small GTP-binding protein Cdc42 is required for nerve growth factor withdrawal-induced neuronal death. Proc Natl Acad Sci U S A 95:3984-3989
Bock BC, Vacratsis PO, Qamirani E, Gallo KA. (2000) Cdc42-induced activation of the mixed-lineage kinase SPRK in vivo. Requirement of the Cdc42/Rac interactive binding motif and changes in phosphorylation. J Biol Chem 275:14231 -14241
Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, Anderson MJ, Arden KC, Blenis J, Greenberg ME. (1999) Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96:857-868
Cantley LC. (2002) The phosphoinositide 3-kinase pathway. Science 296:1655-1657
Carboni S, Antonsson B, Gaillard P, Gotteland JP, Gillon JY, Vitte PA. (2005) Control of death receptor and mitochondrial-dependent apoptosis by c-Jun N-terminal kinase in hippocampal CA1 neurones following global transient ischaemia. J Neurochem 92:1054-1060
Cardone MH, Roy N, Stennicke HR, Salvesen GS, Franke TF, Stanbridge E, Frisch S, Reed JC. (1998) Regulation of cell death protease caspase-9 by phosphorylation. Science 282:1318-1321
Chuang TH, Hahn KM, Lee JD, Danley DE, Bokoch GM. (1997) The small GTPase Cdc42 initiates an apoptotic signaling pathway in Jurkat T lymphocytes. Mol Biol Cell 8:1687-1698
Coso OA, Chiariello M, Yu JC, Teramoto H, Crespo P, Xu N, Miki T, Gutkind JS. (1995) The small GTP-binding proteins Racl and Cdc42 regulate the activity of the JNK/SAPK signaling pathway. Cell 81:1137-1146
Cross TG, Scheel-Toellner D, Henriquez NV, Deacon E, Salmon M, Lord JM. (2000) Serine/threonine protein kinases and apoptosis. Exp Cell Res 256:34-41
Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y, Greenberg ME. (1997) Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 91:231-241
DosReis GA, Borges VM. (2003) Role of Fas-ligand induced apoptosis in pulmonary inflammation and injury. Curr Drug Targets Inflamm Allergy 2:161-167
Du Y, Bock BC, Schachter KA, Chao M, Gallo KA. (2005) Cdc42 induces activation loop phosphorylation and membrane targeting of mixed lineage kinase 3. J Biol Chem 280:42984-42993
Ferrer I, Planas AM. (2003) Signaling of cell death and cell survival following focal cerebral ischemia: life and death struggle in the penumbra. J Neuropathol Exp Neurol 62:329-339
Fukata M, Nakagawa M, Kaibuchi K. (2003) Roles of Rho-family GTPases in cell polarisation and directional migration. Curr Opin Cell Biol 15:590-597
Gallo KA, Johnson GL. (2002) Mixed-lineage kinase control of JNK and p38 MAPK pathways. Nat Rev Mol Cell Biol 3:663-672
Ham J, Eilers A, Whitfield J, Neame SJ, Shah B. (2000) c-Jun and the transcriptional control of neuronal apoptosis. Biochem Pharmacol 60:1015-1021
Harada N, Iimuro Y, Nitta T, Yoshida M, Uchinami H, Nishio T, Hatano E, Yamamoto N, Yamamoto Y, Yamaoka Y. (2003) Inactivation of the small GTPase Racl protects the liver from ischemia/reperfusion injury in the rat. Surgery 134:480-491
Harrington AW, Kim JY, Yoon SO. (2002) Activation of Rac GTPase by p75 is necessary for c-jun N-terminal kinase-mediated apoptosis. J Neurosci 22:156-166
Hasegawa Y, Hamada J, Morioka M, Yano S, Kawano T, Kai Y, Fukunaga K, Ushio Y. (2003) Neuroprotective effect of postischemic administration of sodium orthovanadate in rats with transient middle cerebral artery occlusion. J Cereb Blood Flow Metab 23:1040-1051
Hemmings BA. (1997) Akt signaling: linking membrane events to life and death decisions. Science 275:628-630
Irving EA, Bamford M. (2002) Role of mitogen- and stress-activated kinases in ischemic injury. J Cereb Blood Flow Metab 22:631-647
Ito M, Adachi T, Pimentel DR, Ido Y, Colucci WS. (2004) Statins inhibit beta-adrenergic receptor-stimulated apoptosis in adult rat ventricular myocytes via a Racl-dependent mechanism. Circulation 110:412-418
Kaibuchi K, Kuroda S, Amano M. (1999) Regulation of the cytoskeleton and cell adhesion by the Rho family GTPases in mammalian cells. Annu Rev Biochem 68:459-486
Kawano T, Fukunaga K, Takeuchi Y, Morioka M, Yano S, Hamada J, Ushio Y, Miyamoto E. (2001) Neuroprotective effect of sodium orthovanadate on delayed neuronal death after transient forebrain ischemia in gerbil hippocampus. J Cereb Blood Flow Metab 21:1268-1280
Kim AH, Khursigara G, Sun X, Franke TF, Chao MV. (2001) Akt phosphorylates and negatively regulates apoptosis signal-regulating kinase l. Mol Cell Biol 21.893-901
Kohn AD, Takeuchi F, Roth RA. (1996) Akt, a pleckstrin homology domain containing kinase, is activated primarily by phosphorylation. J Biol Chem 271:21920-21926
Koul D, Jasser SA, Lu Y, Davies MA, Shen R, Shi Y, Mills GB, Yung WK. (2002) Motif analysis of the tumor suppressor gene MMAC/PTEN identifies tyrosines critical for tumor suppression and lipid Phosphatase activity. Oncogene 21:2357-2364
Kuan CY, Whitmarsh AJ, Yang DD, Liao G, Schloemer AJ, Dong C, Bao J, Banasiak KJ, Haddad GG, Flavell RA, Davis RJ, Rakic P. (2003) A critical role of neural-specific JNK3 for ischemic apoptosis. Proc Natl Acad Sci USA 100:15184-15189
Kuan CY, Yang DD, Samanta Roy DR, Davis RJ, Rakic P, Flavell RA. (1999) The Jnk1 and Jnk2 protein kinases are required for regional specific apoptosis during early brain development. Neuron 22:667-676
Kuwana T, Mackey MR, Perkins G, Ellisman MH, Latterich M, Schneiter R, Green DR, Newmeyer DD. (2002) Bid, Bax, and lipids cooperate to form supramolecular openings in the outer mitochondrial membrane. Cell 111:331-342
Kwon T, Kwon DY, Chun J, Kim JH, Kang SS. (2000) Akt protein kinase inhibits Racl-GTP binding through phosphorylation at serine 71 of Racl. J Biol Chem 275:423-428
Leung IW, Lassam N. (2001) The kinase activation loop is the key to mixed lineage kinase-3 activation via both autophosphorylation and hematopoietic progenitor kinase 1 phosphorylation. J Biol Chem 276:1961-1967
Lian Z, Di Cristofano A. (2005) Class reunion: PTEN joins the nuclear crew. Oncogene 24:7394-7400
Lindsten T, Ross AJ, King A, Zong WX, Rathmell JC, Shiels HA, Ulrich E, Waymire KG, Mahar P, Frauwirth K, Chen Y, Wei M, Eng VM, Adelman DM, Simon MC, Ma A, Golden JA, Evan G, Korsmeyer SJ, MacGregor GR, Thompson CB. (2000) The combined functions of proapoptotic Bcl-2 family members bak and bax are essential for normal development of multiple tissues. Mol Cell 6:1389-1399
Love S. (2003) Apoptosis and brain ischaemia. Prog Neuropsychopharmacol Biol Psychiatry 27:267-282
Lu Y, Yu Q, Liu JH, Zhang J, Wang H, Koul D, McMurray JS, Fang X, Yung WK, Siminovitch KA, Mills GB. (2003) Src family protein-tyrosine kinases alter the function of PTEN to regulate phosphatidylinositol 3-kinase/AKT cascades. J Biol Chem 278:40057-40066
Nomura M, Shimizu S, Sugiyama T, Narita M, Jto T, Matsuda H, Tsujimoto Y. (2003) 14-3-3 Interacts directly with and negatively regulates pro-apoptotic Bax. J Biol Chem 278:2058-2065
Okuno S, Saito A, Hayashi T, Chan PH. (2004) The c-Jun N-terminal protein kinase signaling pathway mediates Bax activation and subsequent neuronal apoptosis through interaction with Bim after transient focal cerebral ischemia. J Neurosci 24:7879-7887
Park HS, Kim MS, Huh SH, Park J, Chung J, Kang SS, Choi EJ. (2002) Akt (protein kinase B) negatively regulates SEKI by means of protein phosphorylation. J Biol Chem 277:2573-2578
Putcha GV, Le S, Frank S, Besirli CG, Clark K, Chu B, Alix S, Youle RJ, LaMarche A, Maroney AC, Johnson EM, Jr. (2003) JNK-mediated BIM phosphorylation potentiates BAX-dependent apoptosis. Neuron 38:899-914
Sabapathy K, Jochum W, Hochedlinger K, Chang L, Karin M, Wagner EF. (1999) Defective neural tube morphogenesis and altered apoptosis in the absence of both JNK1 and JNK2. Mech Dev 89:115-124
Saito M, Korsmeyer SJ, Schlesinger PH. (2000) BAX-dependent transport of cytochrome c reconstituted in pure liposomes. Nat Cell Biol 2:553-555
Samuel T, Weber HO, Rauch P, Verdoodt B, Eppel JT, McShea A, Hermeking H, Funk JO. (2001) The G2/M regulator 14-3-3sigma prevents apoptosis through sequestration of Bax. J Biol Chem 276:45201-45206
Shimizu S, Narita M, Tsujimoto Y. (1999) Bcl-2 family proteins regulate the release of apoptogenic cytochrome c by the mitochondrial channel VDAC. Nature 399:483-487
Snider BJ, Gottron FJ, Choi DW. (1999) Apoptosis and necrosis in cerebrovascular disease. Ann N Y A cad Sci 893:243-253
Song JJ, Lee YJ. (2005) Dissociation of Aktl from its negative regulator JIP1 is mediated through the ASK1-MEK-JNK signal transduction pathway during metabolic oxidative stress: a negative feedback loop. J Cell Biol 170:61 -72
Tang Y, Yu J, Field J. (1999) Signals from the Ras, Rac, and Rho GTPases converge on the Pak protein kinase in Rat-1 fibroblasts. Mol Cell Biol 19:1881-1891
Teramoto H, Coso OA, Miyata H, lgishi T, Miki T, Gutkind JS. (1996) Signaling from the small GTP-binding proteins Racl and Cdc42 to the c-Jun N-terminal kinase/stress-activated protein kinase pathway. A role for mixed lineage kinase 3/protein-tyrosine kinase 1, a novel member of the mixed lineage kinase family. J Biol Chem 271:27225-27228
Torres J, Pulido R. (2001) The tumor suppressor PTEN is phosphorylated by the protein kinase CK2 at its C terminus. Implications for PTEN stability to proteasome-mediated degradation. J Biol Chem 276:993-998
Tsuruta F, Sunayama J, Mori Y, Hattori S, Shimizu S, Tsujimoto Y, Yoshioka K, Masuyama N, Gotoh Y. (2004) JNK promotes Bax translocation to mitochondria through phosphorylation of 14-3-3 proteins. Embo 723:1889-1899
Vazquez F, Sellers WR. (2000) The PTEN tumor suppressor protein: an antagonist of phosphoinositide 3-kinase signaling. Biochim Biophys Acta 1470:M21-35
Wei MC, Zong WX, Cheng EH, Lindsten T, Panoutsakopoulou V, Ross AJ, Roth KA, MacGregor GR, Thompson CB, Korsmeyer SJ. (2001) Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science 292:727-730
Woodgett JR. (2005) Recent advances in the protein kinase B signaling pathway. Curr Opin Cell Biol 17:150-157
Yang ZZ, Tschopp O, Baudry A, Dummler B, Hynx D, Hemmings BA. (2004) Physiological functions of protein kinase B/Akt. Biochem Soc Trans 32:350-354
Yuan ZQ, Feldman Rl, Sussman GE, Coppola D, Nicosia SV, Cheng JQ. (2003) AKT2 inhibition of cisplatin-induced JNK/p38 and Bax activation by phosphorylation of ASK1: implication of AKT2 in chemoresistance. J Biol Chem 278:23432-23440
Zhang GY, Zhang QG. (2005) Agents targeting c-Jun N-terminal kinase pathway as potential neuroprotectants. Expert Opin Investig Drugs 14:1373-1383
Zhang H, Gallo KA. (2001) Autoinhibition of mixed lineage kinase 3 through its Src homology 3 domain. J Biol Chem 276:45598-45603
Zheng Z, Zhao H, Steinberg GK, Yenari MA. (2003) Cellular and molecular events underlying ischemia-induced neuronal apoptosis. Drug News Perspect 16:497-503
Zong WX, Lindsten T, Ross AJ, MacGregor GR, Thompson CB. (2001) BH3-only proteins that bind pro-survival Bcl-2 family members fail to induce apoptosis in the absence of Bax and Bak. Genes Dev 15:1481-1486
Alessi DR, Cohen P. (1998) Mechanism of activation and function of protein kinase B. Curr Opin Genet Dev 8:55-62
Bock BC, Vacratsis PO, Qamirani E, Gallo KA. (2000) Cdc42-induced activation of the mixed-lineage kinase SPRK in vivo. Requirement of the Cdc42/Rac interactive binding motif and changes in phosphorylation. J Biol Chem 275:14231 -14241
Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, Anderson MJ, Arden KC, Blenis J, Greenberg ME. (1999) Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96:857-868
Cardone MH, Roy N, Stennicke HR, Salvesen GS, Franke TF, Stanbridge E, Frisch S, Reed JC. (1998) Regulation of cell death protease caspase-9 by phosphorylation. Science 282:1318-1321
Carini R, Grazia De Cesaris M, Splendore R, Baldanzi G, Nitti MP, Alchera E, Filigheddu N, Domenicotti C, Pronzato MA, Graziani A, Albano E. (2004) Role of phosphatidylinositol 3-kinase in the development of hepatocyte preconditioning. Gastroenterology 127:914-923
Das S, Dixon JE, Cho W. (2003) Membrane-binding and activation mechanism of PTEN. Proc Natl Acad Sci USA 100:7491-7496
Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y, Greenberg ME. (1997) Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 91:231 -241
del Peso L, Gonzalez-Garcia M, Page C, Herrera R, Nunez G. (1997) Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt. Science 278:687-689
Dimmeler S, Fleming I, Fisslthaler B, Hermann C, Busse R, Zeiher AM. (1999) Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation. Nature 399:601-605
Gallo KA, Johnson GL. (2002) Mixed-lineage kinase control of JNK and p38 MAPK pathways. Nat Rev Mol Cell Biol 3:663-672
Georgescu MM, Kirsch KH, Akagi T, Shishido T, Hanafusa H. (1999) The tumor-suppressor activity of PTEN is regulated by its carboxyl-terminal region. Proc Natl Acad Sci U S A 96:10182-10187
Gu Z, Jiang Q, Zhang G, Cui Z, Zhu Z. (2000) Diphosphorylation of extracellular signal-regulated kinases and c-Jun N-terminal protein kinases in brain ischemic tolerance in rat. Brain Res 860:157-160
Hashiguchi A, Yano S, Morioka M, Hamada J, Ushio Y, Takeuchi Y, Fukunaga K. (2004) Up-regulation of endothelial nitric oxide synthase via phosphatidylinositol 3-kinase pathway contributes to ischemic tolerance in the CA1 subfield of gerbil hippocampus. J Cereb Blood Flow Metab 24:271-279
Hausenloy DJ, Tsang A, Yellon DM. (2005) The reperfusion injury salvage kinase pathway: a common target for both ischemic preconditioning and postconditioning. Trends Cardiovasc Med 15:69-75
Hemmings BA. (1997) Akt signaling: linking membrane events to life and death decisions. Science 275:628-630
Hlobilkova A, Knillova J, Bartek J, Lukas J, Kolar Z. (2003) The mechanism of action of the tumour suppressor gene PTEN. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 147:19-25
Kis A, Yellon DM, Baxter GF. (2003) Second window of protection following myocardial preconditioning: an essential role for PI3 kinase and p70S6 kinase. J Mol Cell Cardiol 35:1063-1071
Kitagawa K, Matsumoto M, Tagaya M, Hata R, Ueda H, Niinobe M, Handa N, Fukunaga R, Kimura K, Mikoshiba K, et al. (1990) 'Ischemic tolerance' phenomenon found in the brain. Brain Res 528:21-24
Kukekov NV, Xu Z, Greene LA. (2006) Direct interaction of the molecular scaffolds POSH and JIP is required for apoptotic activation of JNKs. J Biol Chem 281:15517-15524
Kwon T, Kwon DY, Chun J, Kim JH, Kang SS. (2000) Akt protein kinase inhibits Racl-GTP binding through phosphorylation at serine 71 of Racl J Biol Chem 275:423-428
Lee SR, Yang KS, Kwon J, Lee C, Jeong W, Rhee SG. (2002) Reversible inactivation of the tumor suppressor PTEN by H2O2. J Biol Chem 277:20336-20342
Leslie NR, Bennett D, Lindsay YE, Stewart H, Gray A, Downes CP. (2003) Redox regulation of PI 3-kinase signalling via inactivation of PTEN. Embo J22:5501-5510
Liu Y, Kato H, Nakata N, Kogure K. (1992) Protection of rat hippocampus against ischemic neuronal damage by pretreatment with sublethal ischemia. Brain Res 586:121-124
Miao B, Yin XH, Pei DS, Zhang QG, Zhang GY. (2005) Neuroprotective effects of preconditioning ischemia on ischemic brain injury through down-regulating activation of JNK1/2 via N-methyl-D-aspartate receptor-mediated Aktl activation. J Biol Chem 280:21693-21699
Murry CE, Jennings RB, Reimer KA. (1986) Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 74:1124-1136
Nakajima T, lwabuchi S, Miyazaki H, Okuma Y, Kuwabara M, Nomura Y, Kawahara K. (2004) Preconditioning prevents ischemia-induced neuronal death through persistent Akt activation in the penumbra region of the rat brain. J Vet Med Sci 66:521-527
Oudit GY, Sun H, Kerfant BG, Crackower MA, Penninger JM, Backx PH. (2004) The role of phosphoinositide-3 kinase and PTEN in cardiovascular physiology and disease. J Mol Cell Cardiol 37:449-471
Seo JH, Ahn Y, Lee SR, Yeol Yeo C, Chung Hur K. (2005) The major target of the endogenously generated reactive oxygen species in response to insulin stimulation is Phosphatase and tensin homolog and not phosphoinositide-3 kinase (PI-3 kinase) in the PI-3 kinase/Akt pathway. Mol Biol Cell 16:348-357
Stambolic V, Suzuki A, de la Pompa JL, Brothers GM, Mirtsos C, Sasaki T, Ruland J, Penninger JM, Siderovski DP, Mak TW. (1998) Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell 95:29-39
Tapon N, Nagata K, Lamarche N, Hall A. (1998) A new rac target POSH is an SH3-containing scaffold protein involved in the JNK and NF-kappaB signalling pathways. Embo J 17:1395-1404
Teramoto H, Coso OA, Miyata H, Igishi T, Miki T, Gutkind JS. (1996) Signaling from the small GTP-binding proteins Racl and Cdc42 to the c-Jun N-terminal kinase/stress-activated protein kinase pathway. A role for mixed lineage kinase 3/protein-tyrosine kinase 1, a novel member of the mixed lineage kinase family. J Biol Chem 271:27225-27228
Tong H, Chen W, Steenbergen C, Murphy E. (2000) Ischemic preconditioning activates phosphatidylinositol-3-kinase upstream of protein kinase C. Circ Res 87:309-315
Torres J, Pulido R. (2001) The tumor suppressor PTEN is phosphorylated by the protein kinase CK2 at its C terminus. Implications for PTEN stability to proteasome-mediated degradation. J Biol Chem 276:993-998
Tsuruta F, Sunayama J, Mori Y, Hattori S, Shimizu S, Tsujimoto Y, Yoshioka K, Masuyama N, Gotoh Y. (2004) JNK promotes Bax translocation to mitochondria through phosphorylation of 14-3-3 proteins. Embo J 23:1889-1899
Vazquez F, Ramaswamy S, Nakamura N, Sellers WR. (2000) Phosphorylation of the PTEN tail regulates protein stability and function. Mol Cell Biol 20:5010-5018
Vazquez F, Sellers WR. (2000) The PTEN tumor suppressor protein: an antagonist of phosphoinositide 3-kinase signaling. Biochim Biophys Acta 1470:M21-35
Xu Z, Kukekov NV, Greene LA. (2003) POSH acts as a scaffold for a multiprotein complex that mediates JNK activation in apoptosis. Embo J22:252-261
Xu Z, Kukekov NV, Greene LA. (2005) Regulation of apoptotic c-Jun N-terminal kinase signaling by a stabilization-based feed-forward loop. Mol Cell Biol 25:9949-9959
Xu Z, Sproul A, Wang W, Kukekov N, Greene LA. (2006) Siahl interacts with the scaffold protein POSH to promote JNK activation and apoptosis. J Biol Chem 281:303-312
Yano S, Morioka M, Fukunaga K, Kawano T, Hara T, Kai Y, Hamada J, Miyamoto E, Ushio Y. (2001) Activation of Akt/protein kinase B contributes to induction of ischemic tolerance in the CA1 subfield of gerbil hippocampus. J Cereb Blood Flow Metab 21:351-360
Yellon DM, Downey JM. (2003) Preconditioning the myocardium: from cellular physiology to clinical cardiology. Physiol Rev 83:1113-1151
Yin XH, Zhang QG, Miao B, Zhang GY. (2005) Neuroprotective effects of preconditioning ischaemia on ischaemic brain injury through inhibition of mixed-lineage kinase 3 via NMDA receptor-mediated Akt 1 activation. J Neurochem 93:1021 -1029