Abstract
Jun and Fos proteins are induced and activated following most physiological and pathophysiological stimuli in the brain. Only few data allow conclusions about distinct functions of AP-1 proteins in neurodegeneration and neuroregeneration, and these functions mainly refer to c-Jun and its activation by JNKs. Apoptotic functions of activated c-Jun affect hippocampal, nigral and primary cultured neurons following excitotoxic stimulation and destruction of the neuron-target-axis including withdrawal of trophic molecules. The inhibition of JNKs might exert neuroprotection by subsequent omission of c-Jun activation. Besides endogenous neuronal functions, the c-Jun/AP-1 proteins can damage the nervous system by upregulation of harmful programs in non-neuronal cells (e.g. microglia) with release of neurodegenerative molecules. In contrast, the differentiation with neurite extension and maturation of neural cells in vitro indicate physiological and potentially neuroprotective functions of c-Jun and JNKs including sensoring for alterations in the cytoskeleton. This review summarizes the multiple molecular interfunctions which are involved in the shift from the physiological role to degenerative effects of the Jun/JNK-axis such as cell type-specific expression and intracellular localization of scaffold proteins and upstream activators, antagonistic phosphatases, interaction with other kinase systems, or the activation of transcription factors competing for binding to JNK proteins and AP-1 DNA elements.
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Abbreviations
- AP-1:
-
activator protein 1 (abbreviation for bothproteins and DNA binding sites)
- ASK 1:
-
apoptosis signal-regulating kinase 1
- CEP-1347:
-
Cephalon compound 1347
- IEGs:
-
immediate-early genes
- IR:
-
immunoreactivity
- JIPs:
-
JNK-interacting proteins
- JNKs:
-
c-Jun N-terminal kinases
- JSAP1:
-
JNK-associated protein 1
- MKKs:
-
MAP kinase kinases
- MKPs:
-
MAP kinase phosphatases
- MLKs:
-
mixed-lineage kinases
- P13-K:
-
phosphatidylinositol-3-kinase
- SAPKs:
-
stress activated protein kinases
- tPA:
-
tissue plasminogen activator
- PAI-1:
-
plasminogen-activatorinhibitor 1.
References
Almendral JM, Sommer D, Macdonald-Bravo H, Burckhardt J, Perera J, Bravo R . 1988 Mol. Cell. Biol. 8: 2140β2148
Anguelova E, Boularand S, Nowicki JP, Benavides J, Smirnova T . 2000 J. Neurosci. Res. 59: 209β217
Arts J, Grimbergen J, Bosma PJ, Rahmsdorf HJ, Kooistra T . 1996 Eur. J. Biochem. 241: 393β402
Bakiri L, Lallemand D, Bossy-Wetzel E, Yaniv M . 2000 EMBO J. 19: 2056β2068
Beer J, Mielke K, Zipp M, Zimmermann M, Herdegen T . 1998 Brain Res. 794: 255β266
Behrens A, Sibilia M, Wagner EF . 1999 Nat. Genet. 21: 326β329
Brecht S, Simler S, Vergnes M, Mielke K, Marescaux C, Herdegen T . 1999 Brain Res. Mol. Brain Res. 68: 101β108
Boss V, Roback JD, Young AN, Roback LJ, Weisenhorn DM, Medina-Flores R, Wainer BH . 2001 J. Neurosci. 21: 18β26
Carboni L, Carletti R, Tacconi S, Corti C, Ferraguti F . 1998 Brain Res. Mol. Brain Res. 60: 57β68
Carletti R, Tacconi S, Bettini E, Ferraguti F . 1995 Neuroscience 69: 1103β1110
Chen J, Kelz MB, Hope BT, Nakabeppu Y, Nestler EJ . 1997 J. Neurosci. 17: 4933β4941
Chihab R, Ferry C, Koziel V, Monin P, Daval JL . 1998 Brain Res. Mol. Brain Res. 63: 105β120
Coffer P, Lutticken C, van Puijenbroek A, Klop-de Jonge M, Horn F, Kruijer W . 1995 Oncogene 10: 985β994
Coffey ET, Hongisto V, Dickens M, Davis RJ, Courtney MJ . 2000 J. Neurosci. 20: 7602β7613
Cruzalegui FH, Hardingham GE, Bading H . 1999 EMBO J. 18: 1335β1344
Deng T, Karin M . 1994 Nature 371: 171β175
Dickens M, Rogers JS, Cavanagh J, Raitano A, Xia Z, Halpern JR, Greenberg ME, Sawyers CL, Davis RJ . 1997 Science 277: 693β696
Edelstein K, Beaule C, D'Abramo R, Amir S . 2000 Brain Res. 870: 54β65
Eilers A, Whitfield J, Babij C, Rubin LL, Ham J . 1998 J. Neurosci. 18: 1713β1724
Elliott RC, Gall CM . 2000 J. Neurosci. 20: 2142β2149
Falvo JV, Uglialoro AM, Brinkman BM, Merika M, Parekh BS, Tsai EY, King HC, Morielli AD, Peralta EG, Maniatis T, Thanos D, Goldfeld AE . 2000 Mol. Cell. Biol. 20: 2239β2247
Fernyhough P, Gallagher A, Averill SA, Priestley JV, Hounsom L, Patel J, Tomlinson DR . 1999 Diabetes 48: 881β889
Ferrell JE . 2000 Science's STKE 52: 1β3
Ferrer I, Planas AM, Pozas E . 1997 Neuroscience 80: 449β458
Gass P, Herdegen T, Bravo R, Kiessling M . 1993 Eur. J. Neurosci. 5: 933β943
Giasson BI, Bruening W, Durham HD, Mushynski WE . 1999 J. Neurochem. 72: 1081β1087
Gingrich MB, Traynelis SF . 2000 Trends Neurosci. 23: 399β407
Gonzalez MV, Jimenez B, Berciano MT, Gonzalez-Sancho JM, Caelles C, Lafarga M, Munoz A . 2000 J. Cell. Biol. 150: 1199β1208
Grimm R, Schicknick H, Riede I, Gundelfinger ED, Herdegen T, Zuschratter W, Tischmeyer W . 1997 Learn. Mem. 3: 402β413
Gupta S, Barrett T, Whitmarsh AJ, Cavanagh J, Sluss HK, Derijard B, Davis RJ . 1996 EMBO J. 15: 2760β2770
Ham J, Babij C, Whitfield J, Pfarr CM, Lallemand D, Yaniv M, Rubin LL . 1995 Neuron 14: 927β939
Han J, Jiang Y, Li Z, Kravchenko VV, Ulevitch RJ . 1997 Nature 386: 296β299
Harada J, Sugimoto M . 1999 Jpn. J. Pharmacol. 79: 369β378
Hata R, Maeda K, Hermann D, Mies G, Hossmann KA . 2000 J. Cereb. Blood Flow Metab. 20: 306β315
Hayashi T, Sakai K, Sasaki C, Zhang WR, Warita H, Abe K . 2000 Neurosci. Lett. 284: 195β199
Herdegen T, Claret FX, Kallunki T, Martin-Villalba A, Winter C, Hunter T, Karin M . 1998 J. Neurosci. 18: 5124β5135
Herdegen T, Leah JD . 1998 Brain Res. Brain Res. Rev. 28: 370β490
Herdegen T, Skene P, Bahr M . 1997 Trends Neurosci. 20: 227β231
Herzog KH, Chen SC, Morgan JI . 1999 J. Neurosci. 19: 4349β4359
Hilberg F, Aguzzi A, Howells N, Wagner EF . 1993 Nature 365: 179β181
Houle JD, Ye JH . 1999 Neuroscience 94: 929β936
Hsieh TF, Simler S, Vergnes M, Gass P, Marescaux C, Wiegand SJ, Zimmermann M, Herdegen T . 1998 Exp. Neurol. 149: 161β174
Ichijo H . 1999 Oncogene 18: 6087β6093
Ikeuchi T, Shimoke K, Kubo T, Yamada M, Hatanaka H . 1998 Hum. Cell 11: 125β140
Ito M, Yoshioka K, Akechi M, Yamashita S, Takamatsu N, Sugiyama K, Hibi M, Nakabeppu Y, Shiba T, Yamamoto KI . 1999 Mol. Cell. Biol. 19: 7539β7548
Jones KJ . 1993 Brain Res. Bull. 30: 491β498
Kallunki T, Deng T, Hibi M, Karin M . 1996 Cell 87: 929β939
Kanamoto T, Mota M, Takeda K, Rubin LL, Miyazono K, Ichijo H, Bazenet CE . 2000 Mol. Cell. Biol. 20: 196β204
Kenney AM, Kocsis JD . 1998 J. Neurosci. 18: 1318β1328
Keyse SM . 1998 Semin. Cell. Dev. Biol. 9: 143β152
Kim IJ, Lee KW, Park BY, Lee JK, Park J, Choi IY, Eom SJ, Chang TS, Kim MJ, Yeom YI, Chang SK, Lee YD, Choi EJ, Han PL . 1999 J. Neurochem. 72: 1335β1343
Kirch HC, Flaswinkel S, Rumpf H, Brockmann D, Esche H . 1999 Oncogene 18: 2728β2738
Kita Y, Kimura KD, Kobayashi M, Ihara S, Kaibuchi K, Kuroda S, Ui M, Iba H, Konishi H, Kikkawa U, Nagata S, Fukui Y . 1998 J. Cell. Sci. 111: 907β915
Kolbus A, Herr I, Schreiber M, Debatin KM, Wagner EF, Angel P . 2000 Mol. Cell. Biol. 20: 575β582
Kreutz MR, Bien A, Vorwerk CK, Bockers TM, Seidenbecher CI, Tischmeyer W, Sabel BA . 1999 Brain Res. Mol. Brain Res. 69: 232β241
Kuboki Y, Ito M, Takamatsu N, Yamamoto K, Shiba T, Yoshioka K . 2000 J. Biol. Chem. 275: 39815β39818
Kurokawa T, Katai N, Shibuki H, Kuroiwa S, Kurimoto Y, Nakayama C, Yoshimura N . 1999 Invest. Ophthalmol. Vis. Sci. 40: 3006β3011
Lallemand D, Ham J, Garbay S, Bakiri L, Traincard F, Jeannequin O, Pfarr CM, Yaniv M . 1998 EMBO J. 17: 5615β5626
Leah JD, Herdegen T, Bravo R . 1991 Brain Res. 566: 198β207
Lee JK, Park J, Lee YD, Lee SH, Han PL . 1999 Brain Res. Mol. Brain Res. 70: 116β124
Leppa S, Bohmann D . 1999 Oncogene 18: 6158β6162
Leppa S, Saffrich R, Ansorge W, Bohmann D . 1998 EMBO J. 17: 4404β4413
Levresse V, Butterfield L, Zentrich E, Heasley LE . 2000 J. Neurosci. Res. 62: 799β808
Lipton P . 1999 Physiol. Rev. 79: 1431β1568
Liu YF, Dorow D, Marshall J . 2000 J. Biol. Chem. 275: 19035β19040
Low W, Smith A, Ashworth A, Collins M . 1999 Oncogene 18: 3737β3741
Mao Z, Bonni A, Xia F, Nadal-Vicens M, Greenberg ME . 1999 Science 286: 785β790
Marinissen MJ, Chiariello M, Pallante M, Gutkind JS . 1999 Mol. Cell. Biol. 19: 4289β4301
Maroney AC, Glicksman MA, Basma AN, Walton KM, Knight Jr. E, Murphy CA, Bartlett BA, Finn JP, Angeles T, Matsuda Y, Neff NT, Dionne CA . 1998 J. Neurosci. 18: 104β111
Martin JH, Mohit AA, Miller CA . 1996 Brain Res. Mol. Brain Res. 35: 47β57
Martin-Villalba A, Herr I, Jeremias I, Hahne M, Brandt R, Vogel J, Schenkel J, Herdegen T, Debatin KM . 1999 J. Neurosci. 19: 3809β3817
Marushige K, Marushige Y . 1999 Anticancer Res. 19: 3865β3871
McDonald PH, Chow CW, Miller WE, Laporte SA, Field ME, Lin FT, Davis RJ, Lefkowitz RJ . 2000 Science 290: 1574β1577
Meriin AB, Yaglom JA, Gabai VL, Zon L, Ganiatsas S, Mosser DD, Sherman MY . 1999 Mol. Cell. Biol. 19: 2547β2555
Mielke K, Brecht S, Dorst A, Herdegen T . 1999 Neuroscience 91: 471β483
Mielke K, Damm A, Yang DD, Herdegen T . 2000 Brain Res. Mol. Brain Res. 75: 128β137
Mielke K, Herdegen T . 2000 Prog. Neurobiol. 61: 45β60
Migheli A, Piva R, Atzori C, Troost D, Schiffer D . 1997 J. Neuropathol. Exp. Neurol. 56: 1314β1322
Muda M, Theodosiou A, Rodrigues N, Boschert U, Camps M, Gillieron C, Davies K, Ashworth A, Arkinstall S . 1996 J. Biol. Chem. 271: 27205β27208
Mulle C, Sailer A, Perez-Otano I, Dickinson-Anson H, Castillo PE, Bureau I, Maron C, Gage FH, Mann JR, Bettler B, Heinemann SF . 1998 Nature 392: 601β605
Musti AM, Treier M, Bohmann D . 1997 Science 275: 400β402
Nagata K, Puls A, Futter C, Aspenstrom P, Schaefer E, Nakata T, Hirokawa N, Hall A . 1998 EMBO J. 17: 149β158
Nakahara S, Yone K, Sakou T, Wada S, Nagamine T, Niiyama T, Ichijo H . 1999 J. Neuropathol. Exp. Neurol. 58: 442β450
Namgung U, Xia Z . 2000 J. Neurosci. 20: 6442β6451
Napieralski JA, Raghupathi R, Mclntosh TK . 1999 Brain Res. Mol. Brain Res. 71: 78β86
Oo TF, Henchcliffe C, James D, Burke RE . 1999 J. Neurochem. 72: 557β564
Oren A, Herschkovitz A, Ben-Dror I, Holdengreber V, Ben-Shaul Y, Seger R, Vardimon L . 1999 Mol. Cell. Biol. 19: 1742β1750
Ozawa H, Shioda S, Dohi K, Matsumoto H, Mizushima H, Zhou CJ, Funahashi H, Nakai Y, Nakajo S, Matsumoto K . 1999 Neurosci. Lett. 262: 57β60
Paratcha G, de Stein ML, Szapiro G, Lopez M, Bevilaqua L, Cammarota M, de Iraldi AP, Izquierdo I, Medina JH . 2000 Brain Res. Mol. Brain Res. 78: 120β130
Pellet JB, Haefliger JA, Staple JK, Widmann C, Welker E, Hirling H, Bonny C, Nicod P, Catsicas S, Waeber G, Riederer BM . 2000 Eur. J. Neurosci. 12: 621β632
Pena E, Berciano MT, Fernandez R, Crespo P, Lafarga M . 2000 Exp. Cell. Res. 256: 179β191
Pennypacker KR, Eidizadeh S, Kassed CA, O'Callaghan JP, Sanberg PR, Willing AE . 2000 Neurosci. Lett. 289: 1β4
Perez O, Ntilde OI, Mandelzys A, Morgan JI . 1998 Brain Res. Mol. Brain Res. 53: 41β52
Purkiss RJ, Legg MD, Hunt SP, Davies SW . 1993 Eur. J. Neurosci. 5: 1653β1662
Raivich G, Bohatschek M, Kloss CU, Werner A, Jones LL, Kreutzberg GW . 1999 Brain Res. Brain Res. Rev. 30: 77β105
Rebollo A, Dumoutier L, Renauld JC, Zaballos A, Ayllon V, Martinez AC . 2000 Mol. Cell. Biol. 20: 3407β3416
Reynolds CH, Betts JC, Blackstock WP, Nebreda AR, Anderton BH . 2000 J. Neurochem. 74: 1587β1595
Rizzo MT, Leaver AH, Yu WM, Kovacs RJ . 1999 Prostaglandins Leukot. Essent. Fatty Acids 60: 187β198
Robinson GA . 1995 Brain Res. Mol. Brain Res. 30: 61β69
Sabapathy K, Hu Y, Kallunki T, Schreiber M, David JP, Jochum W, Wagner EF, Karin M . 1999 Curr. Biol. 9: 116β125
Sadot E, Jaaro H, Seger R, Ginzburg I . 1998 J. Neurochem. 70: 428β431
Salehi M, Barron M, Merry BJ, Goyns MH . 1999 Mech. Ageing Dev. 107: 61β71
Saporito MS, Thomas BA, Scott RW . 2000 J. Neurochem. 75: 1200β1208
Schauwecker PE . 2000 Brain Res. 884: 116β128
Sgambato V, Vanhoutte P, Pages C, Rogard M, Hipskind R, Besson MJ, Caboche J . 1998 J. Neurosci. 18: 214β226
Sheng M, Pak DT . 2000 Annu. Rev. Physiol. 62: 755β778
Skinner M, Qu S, Moore C, Wisdom R . 1997 Mol. Cell. Biol. 17: 2372β2380
Small DL, Monette R, Comas T, Fournier M, Morley P . 1999 Brain Res. 842: 376β383
Sommer C, Gass P, Kiessling M . 1995 Brain Pathol. 5: 135β144
Standen CL, Brownlees J, Grierson AJ, Kesavapany S, Lau KF, McLoughlin DM, Miller CC . 2001 J. Neurochem. 76: 316β320
Steward O, Schauwecker PE, Guth L, Zhang Z, Fujiki M, Inman D, Wrathall J, Kempermann G, Gage FH, Saatman KE, Raghupathi R, Mclntosh T . 1999 Exp. Neurol. 157: 19β42
Sugino T, Nozaki K, Takagi Y, Hattori I, Hashimoto N, Moriguchi T, Nishida E . 2000 J. Neurosci. 20: 4506β4514
Telfeian AE, Federoff HJ, Leone P, During MJ, Williamson A . 2000 Neurobiol. Dis. 7: 362β374
Timsit S, Rivera S, Ouaghi P, Guischard F, Tremblay E, Ben-Ari Y, Khrestchatisky M . 1999 Eur. J. Neurosci. 11: 263β278
Tsirka SE, Gualandris A, Amaral DG, Strickland S . 1995 Nature 377: 340β344
Tsurumi C, Ishida N, Tamura T, Kakizuka A, Nishida E, Okumura E, Kishimoto T, Inagaki M, Okazaki K, Sagata N et al . 1995 Mol. Cell. Biol. 15: 5682β5687
Vaudano E, Campbell G, Hunt SP, Lieberman AR . 1998 Eur. J. Neurosci. 10: 2644β2656
Virdee K, Bannister AJ, Hunt SP, Tolkovsky AM . 1997 J. Neurochem. 69: 550β561
Wang TH, Wang HS, Ichijo H, Giannakakou P, Foster JS, Fojo T, Wimalasena J . 1998 J. Biol. Chem. 273: 4928β4936
Watanabe Y, Johnson RS, Butler LS, Binder DK, Spiegelman BM, Papaioannou VE, McNamara JO . 1996 J. Neurosci. 16: 3827β3836
Winter C, Schenkel J, Zimmermann M, Herdegen T . 1998 Brain Res. 801: 198β205
Wollnik F, Brysch W, Uhlmann E, Gillardon F, Bravo R, Zimmermann M, Schlingensiepen KH, Herdegen T . 1995 Eur. J. Neurosci. 7: 388β393
Xia Z, Dickens M, Raingeaud J, Davis RJ, Greenberg ME . 1995 Science 270: 1326β1331
Xu J, Kim GM, Ahmed SH, Yan P, Xu XM, Hsu CY . 2001 J. Neurosci. 21: 92β97
Xu X, Raber J, Yang D, Su B, Mucke L . 1997 Proc. Natl. Acad. Sci. USA 94: 12655β12660
Yang DD, Conze D, Whitmarsh AJ, Barrett T, Davis RJ, Rincon M, Flavell RA . 1998 Immunity 9: 575β585
Yang DD, Kuan CY, Whitmarsh AJ, Rincon M, Zheng TS, Davis RJ, Rakic P, Flavell RA . 1997 Nature 389: 865β870
Yasuda J, Whitmarsh AJ, Cavanagh J, Sharma M, Davis RJ . 1999 Mol. Cell. Biol. 19: 7245β7254
Yujiri T, Fanger GR, Garrington TP, Schlesinger TK, Gibson S, Johnson GL . 1999 J. Biol. Chem. 274: 12605β12610
Zhang Y, Zhou L, Miller CA . 1998 Proc. Natl. Acad. Sci. USA 95: 2586β2591
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Herdegen, T., Waetzig, V. AP-1 proteins in the adult brain: facts and fiction about effectors of neuroprotection and neurodegeneration. Oncogene 20, 2424β2437 (2001). https://doi.org/10.1038/sj.onc.1204387
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