Abstract
Neuronal viability is maintained through a complex interacting network of signaling pathways that can be perturbed in response to a multitude of cellular stresses. A shift in the balance of signaling pathways after stress or in response to pathology can have drastic consequences for the function or the fate of a neuron. There is significant evidence that acutely injured and degenerating neurons may die by an active mechanism of cell death. This process involves the activation of discrete signaling pathways that ultimately compromise mitochondrial structure, energy metabolism and nuclear integrity. In this review we examine recent evidence pertaining to the presence and activation of anti-and pro-cell death regulatory pathways in nervous system injury and degeneration.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Walczak H, Krammer PH. The CD95 (APO-1/Fas) and the TRAIL (APO-2L) apoptosis systems. Exp Cell Res 2000; 256:58–66.
Bachmann I, Mor G, Nilsen J, Eliza M, Nitsch R, Naftolin F. FasL (CD95L, Apo1L) is expressed in the normal rat and human brain: Evidence for the existence of an immunological brain barrier. Glia 1999; 27:62–74.
Felderhoff-Mueser U, Taylor DL, Greenwood K, Kozma M, Stibenz D, Joashi UC et al. Fas/CD95/APO-1 can function as a death receptor for neuronal cells in vitro and in vivo and is upregulated following cerebral hypoxic-ischemic injury to the developing rat brain. Brain Pathol 2000; 10:17–29.
Raoul C, Henderson CE, Pettmann B. Programmed cell death of embryonic motoneurons triggered through the Fas death receptor. J Cell Biol 1999; 147:1049–1062
Matsushita K, Wu Y, Qiu J, Lang-Lazdunski L, Hirt L, Waeber C et al. Fas receptor and neuronal cell death after spinal cord ischemia. J Neurosci 2000; 20:6879–6887.
Martin-Villalba A, Herr I, Jeremias I, Hahne M, Brandt R, Vogel J et al. CD95 ligand (FasL/APO-1L) and tumor necrosis factor-related apoptosis-inducing ligand mediate ischemiainduced apoptosis in neurons. J Neurosci 1999; 19:3809–3817.
Rosenbaum DM, Gupta G, D Amore J, Singh M, Weidenheim K, Zhang H et al. Fas (CD95/ APO-1) plays a role in the pathophysiology of focal cerebral ischemia. J Neurosci Res 2000; 61:686–692.
Elovaara I, Sabri F, Gray F, Alafuzoff I, Chiodi F. Upregulated expression of Fas and Fas ligand in brain through the spectrum of HIV-1 infection. Acta Neuropathol (Berl) 1999; 98:355–362.
Kaul M, Garden GA, Lipton SA. Pathways to neuronal injury and apoptosis in HIV-associated dementia. Nature 2001; 410:988–994.
Sharma K, Wang RX, Zhang LY, Yin DL, Luo XY, Solomon JC et al. Death the Fas way: Regulation and pathophysiology of CD95 and its ligand. Pharmacol Ther 2000; 88:333–347.
Raoul C, Pettmann B, Henderson CE. Active killing of neurons during development and following stress: a role for p75(NTR) and Fas? Curr Opin Neurobiol 2000; 10:111–117.
Varfolomeev EE, Schuchmann M, Luria V, Chiannilkulchai N, Beckmann JS, Mett IL et al. Targeted disruption of the mouse Caspase 8 gene ablates cell death induction by the TNF receptors, Fas/Apol, and DR3 and is lethal prenatally. Immunity 1998; 9:267–276.
Li H, Zhu H, Xu CJ, Yuan J. Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 1998; 94:491–501.
Scaffidi C, Fulda S, Srinivasan A, Friesen C, Li F, Tomaselli KJ et al. Two CD95 (APO-1/ Fas) signaling pathways. Embo J 1998; 17:1675–1687.
Bratton SB, MacFarlane M, Cain K, Cohen GM. Protein complexes activate distinct caspase cascades in death receptor and stress-induced apoptosis. Exp Cell Res 2000; 256:27–33.
Wang J, Zheng L, Lobito A, Chan FK, Dale J, Sneller M et al. Inherited human Caspase 10 mutations underlie defective lymphocyte and dendritic cell apoptosis in autoimmune lymphoproliferative syndrome type II. Cell 1999; 98:47–58.
Reimann-Philipp U, Ovase R, Weigel PH, Grammas P. Mechanisms of cell death in primary cortical neurons and PC12 cells. J Neurosci Res 2001; 64:654–660.
Barker V, Middleton G, Davey F, Davies AM. TNFalpha contributes to the death of NGFdependent neurons during development. Nat Neurosci 2001; 4:1194–1198.
Kim GM, Xu J, Song SK, Yan P, Ku G, Xu XM et al. Tumor necrosis factor receptor deletion reduces nuclear factor-kappaB activation, cellular inhibitor of apoptosis protein 2 expression, and functional recovery after traumatic spinal cord injury. J Neurosci 2001; 21:6617–6625.
Lin Y, Devin A, Cook A, Keane MM, Kelliher M, Lipkowitz S et al. The death domain kinase RIP is essential for TRAIL (Apo2L)-induced activation of IkappaB kinase and c-Jun N-terminal kinase. Mol Cell Biol 2000; 20: 6638–6645.
Wajant H, Henkler F, Scheurich P. The TNF-reçeptor-associated factor family: Scaffold molecules for cytokine receptors, kinases and their regulators. Cell Signal 2001; 13:389–400.
Baud V, Karin M. Signal transduction by tumor necrosis factor and its relatives. Trends Cell Biol 2001; 11:372–377.
Grell M, Zimmermann G, Gottfried E, Chen CM, Grunwald U, Huang DC et al. Induction of cell death by tumour necrosis factor (TNF) receptor 2, CD40 and CD30: A role for TNFRI activation by endogenous membrane-anchored TNF. Embo J 1999; 18:3034–3043.
Griffith TS, Lynch DH. TRAIL: A molecule with multiple receptors and control mechanisms. Curr Opin Immunol 1998; 10:559–563.
Wiley SR, Schooley K, Smolak PJ, Din WS, Huang CP, Nicholl JK et al. Identification and characterization of a new member of the TNF family that induces apoptosis. Immunity 1995; 3:673–682.
Sheikh MS, Fomace AJ, Jr. Death and decoy receptors and p53-mediated apoptosis. Leukemia 2000; 14:1509–1513.
Degli-Esposti MA, Dougall WC, Smolak PJ, Waugh JY, Smith CA, Goodwin RG. The novel receptor TRAIL-R4 induces NF-kappaB and protects against TRAIL-mediated apoptosis, yet retains an incomplete death domain. Immunity 1997; 7:813–820.
Ashkenazi A, Pai RC, Fong S, Leung S, Lawrence DA, Marsters SA et al. Safety and antitumor activity of recombinant soluble Apo2 ligand. J Clin Invest 1999; 104:155–162.
Zhang XD, Nguyen T, Thomas WD, Sanders JE, Hersey P. Mechanisms of resistance of normal cells to TRAIL induced apoptosis vary between different cell types. FEES Lett 2000; 482:193–199.
Jo M, Kim TH, Seol DW, Esplen JE, Dorko K, Billiar TR et al. Apoptosis induced in normal human hepatocytes by tumor necrosis factor-related apoptosis-inducing ligand. Nat Med 2000; 6:564–567.
Frank S, Kohler U, Schackert G, Schackert HK. Expression of TRAIL and its receptors in human brain tumors. Biochem Biophys Res Commun 1999; 257:454–459.
Nitsch R, Bechmann I, Deisz RA, Haas D, Lehmann TN, Wendling U et al. Human brain-cell death induced by tumour-necrosis-factor-related apoptosis-inducing ligand (TRAIL). Lancet 2000; 356:827–828.
Eggert A, Grotzer MA, Zuzak TJ, Wiewrodt BR, Ikegaki N, Brodeur GM. Resistance to TRAIL-induced apoptosis in neuroblastoma cells correlates with a loss of caspase-8 expression. Med Pediatr Oncol 2000; 35:603–607.
Sprick MR, Weigand MA, Rieser E, Rauch CT, Juo P, Blenis J et al. FADD/MORT1 and caspase-8 are recruited to TRAIL receptors 1 and 2 and are essential for apoptosis mediated by TRAIL receptor 2. Immunity 2000; 12:599–609.
Mariani SM, Matiba B, Armandola EA, ‘Crammer PH. Interleukin 1 beta-converting enzyme related proteases/caspases are involved in TRAIL-induced apoptosis of myeloma and leukemia cells. J Cell Biol 1997; 137:221–229.
Kuang AA, Diehl GE, Zhang J, Winoto A. FADD is required for DR4- and DR5-mediated apoptosis: lack of trail-induced apoptosis in FADD-deficient mouse embryonic fibroblasts. J Biol Chem 2000; 275:25065–25068.
Meng RD, McDonald ER, 3rd, Sheikh MS, Fornace AJ, Jr., El-Deiry WS. The TRAIL decoy receptor TRUNDD (DcR2, TRAIL-R4) is induced by adenovirus-p53 overexpression and can delay TRAIL-, p53-, and KILLER/DR5-dependent colon cancer apoptosis. Mol Ther 2000; 1:130–144.
Meng RD, El-Deiry WS. p53-independent upregulation of KILLER/DR5 TRAIL receptor expression by glucocorticoids and interferon-gamma. Exp Cell Res 2001; 262:154–169.
Sheikh MS, Huang Y, Fernandez-Salas EA, El-Deiry WS, Friess H, Amundson S et al. The antiapoptotic decoy receptor TRID/TRAIL-R3 is a p53-regulated DNA damage-inducible gene that is overexpressed in primary tumors of the gastrointestinal tract. Oncogene 1999; 18:4153–4159.
Pan G, Ni J, Wei YF, Yu G, Gentz R, Dixit VM. An antagonist decoy receptor and a death domain-containing receptor for TRAIL. Science 1997; 277:815–818.
Sheridan JP, Marsters SA, Pitti RM, Gurney A, Skubatch M, Baldwin D et al. Control of TRAIL-induced apoptosis by a family of signaling and decoy receptors. Science 1997; 277:818–821.
Griffith TS, Rauch CT, Smolak PJ, Waugh JY, Boiani N, Lynch DH et al. Functional analysis of TRAIL receptors using monoclonal antibodies. J Immunol 1999; 162:2597–2605.
Zhang XD, Franco A, Myers K, Gray C, Nguyen T, Hersey P. Relation of TNF-related apoptosis-inducing ligand (TRAIL) receptor and FLICE-inhibitory protein expression to TRAIL-induced apoptosis of melanoma. Cancer Res 1999; 59:2747–2753.
Sedel F, Bechade C, Triller A. Nerve growth factor (NGF) induces motoneuron apoptosis in rat embryonic spinal cord in vitro. Eur J Neurosci 1999; 11:3904–3912.
Wiese S, Metzger F, Holtmann B, Sendtner M. The role of p75NTR in modulating neurotrophin survival effects in developing motoneurons. Eur J Neurosci 1999; 11:1668–1676.
Ferri CC, Moore FA, Bisby MA. Effects of facial nerve injury on mouse motoneurons lacking the p75 low-affinity neurotrophin receptor. J Neurobiol 1998; 34:1–9.
Bamji SX, Majdan M, Pozniak CD, Belliveau DJ, Aloyz R, Kohn et al. The p75 neurotrophin receptor mediates neuronal apoptosis and is essential for naturally occurring sympathetic neuron death. J Cell Biol 1998; 140:911–923.
Frade JM, Barde YA. Genetic evidence for cell death mediated by nerve growth factor and the neurotrophin receptor p75 in the developing mouse retina and spinal cord. Development 1999; 126:683–690.
Casaccia-Bonnefil P, Kong H, Chao MV. Neurotrophins: the biological paradox of survival factors eliciting apoptosis. Cell Death Differ 1998; 5:357–364.
Wang X, Bauer JH, Li Y, Shao Z, Zetoune FS, Cattaneo E et al. Characterization of a p75(NTR) apoptotic signaling pathway using a novel cellular model. J Biol Chem 2001; 276:33812–33820.
Casademunt E, Carter BD, Benzel I, Frade JM, Dechant G, Barde YA, The zinc finger protein NRIF interacts with the neurotrophin receptor p75(NTR) and participates in programmed cell death. Embo J 1999; 18:6050–6061.
Mukai J, Hachiya T, Shoji-Hoshino S, Kimura MT, Nadano D, Suvanto P et al. NADE, a p75NTR-associated cell death executor, is involved in signal transduction mediated by the common neurotrophin receptor p75NTR. J Biol Chem 2000; 275:17566–17570.
Salehi AH, Roux PP, Kubu CJ, Zeindler C, Bhakar A, Tannis LL et al. NRAGE, a novel MAGE protein, interacts with the p75 neurotrophin receptor and facilitates nerve growth factor-dependent apoptosis. Neuron 2000; 27:279–288.
Khursigara G, Bertin J, Yana H, Moffett H, DiStefano PS, Chao MV. A prosurvival function for the p75 receptor death domain mediated via the caspase recruitment domain receptor-interacting protein 2. J Neurosci 2001; 21:5854–5863.
Yao R, Cooper GM, Requirement for phosphatidylinosito1–3 kinase in the prevention of apoptosis by nerve growth factor. Science 1995; 267:2003–2006.
Crowder RJ, Freeman RS. Phosphatidylinositol 3-kinase and Akt protein kinase are necessary and sufficient for the survival of nerve growth factor-dependent sympathetic neurons. J Neurosci 1998; 18:2933–2943.
Ghosh A, Greenberg ME. Distinct roles for bFGF and NT-3 in the regulation of cortical neurogenesis. Neuron 1995; 15:89–103.
Kuruvilla R, Ye H, Ginty DD. Spatially and functionally distinct roles of the PI3-K effector pathway during NGF signaling in sympathetic neurons. Neuron 2000; 27:499–512.
Segal RA, Greenberg ME. Intracellular signaling pathways activated by neurotrophic factors. Annu Rev Neurosci 1996; 19:463–489
Brunet A, Datta SR, Greenberg ME. Transcription-dependent and -independent control of neuronal survival by the PI3K-Akt signaling pathway. Curr Opin Neurobiol 2001; 11:297–305.
Holgado-Madruga M, Moscatello DK, Emlet DR, Dieterich R, Wong AJ. Grb2-associated binder-1 mediates phosphatidylinositol 3-kinase activation and the promotion of cell survival by nerve growth factor. Proc Natl Acad Sci USA 1997; 94:12419–12424.
Kauffmann-Zeh A, Rodriguez-Viciana P, Ulrich E, Gilbert C, Coffer P, Downward J et al. Suppression of c-Myc-induced apoptosis by Ras signalling through PI(3)K and’PKB. Nature 1997; 385:544–548.
Dhand R, Hara K, Hiles I, Bax B, Gout I, Panayotou G et al. PI 3-kinase: structural and functional analysis of intersubunit interactions. Embo J 1994; 13:511–521.
Hu Q, Klippel A, Muslin AJ, Fantl WJ, Williams LT. Ras-dependent induction of cellular responses by constitutively active phosphatidylinositol-3 kinase. Science 1995; 268:100–102.
Dudek H, Datta SR, Franke TF, Birnbaum MJ, Yao R, Cooper GM et al. Regulation of neuronal survival by the serine-threonine protein kinase Akt. Science 1997; 275:661–665.
Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS et al. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 1999; 96:857–868.
Yamaguchi A, Tamatani M, Matsuzaki H, Namikawa K, Kiyama H, Vitek MP et al. Akt activation protects hippocampal neurons from apoptosis by inhibiting transcriptional activity of p53. J Biol Chem 2001; 276:5256–5264.
Bonni A, Brunet A, West AE, Datta SR, Takasu MA, Greenberg ME. Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms. Science 1999; 286:1358–1362.
Maggirwar SB, Sarmiere PD, Dewhurst S, Freeman RS. Nerve growth factor-dependent activation of NF-kappaB contributes to survival of sympathetic neurons. J Neurosci 1998; 18:10356–10365.
Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y et al. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 1997; 91:231–241.
Cardone MH, Roy N, Stennicke HR, Salvesen GS, Franke TF, Stanbridge E et al. Regulation of cell death protease caspase-9 by phosphorylation. Science 1998; 282:1318–1321.
Hetman M, Cavanaugh JE, Kimelman D, Xia Z. Role of glycogen synthase kinase-3beta in neuronal apoptosis induced by trophic withdrawal. J Neurosci 2000; 20:2567–2574.
Xia Z, Dickens M, Raingeaud J, Davis RJ, Greenberg ME. Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Science 1995; 270:1326–1331.
Impey S, Obrietan K, Storm DR. Making new connections: role of ERK/MAP kinase signaling in neuronal plasticity. Neuron 1999; 23:11–14.
Sweatt JD. The neuronal MAP kinase cascade: a biochemical signal integration system subserving synaptic plasticity and memory. J Neurochem 2001; 76:1–10.
Murray B, Alessandrini A, Cole AJ,YeeAG, Furshpan EJ. Inhibition of the p44/42 MAP kinase pathway protects hippocampal neurons in a cell-culture model of seizure activity. Proc Natl Acad Sci USA 1998; 95:11975–11980.
Kulich SM, Chu CT. Sustained extracellular signal-regulated kinase activation by 6hydroxydopamine: Implications for Parkinson s disease. J Neurochem 2001; 77:1058–1066.
Stanciu M, DeFranco DB. Prolonged nuclear retention of activated ERK promotes cell death generated by oxidative toxicity or proteasome inhibition in a neuronal cell line. J Biol Chem 2002; 277:4010–4017.
Abe MK, Kahle KT, Saelzler MP, Orth K, Dixon JE, Rosner MR. ERK7 is an autoactivated member of the MAPK family. J Biol Chem 2001; 276:21272–21279.
Hetman M, Xia Z. Signaling pathways mediating anti-apoptotic action of neurotrophins. Acta Neurobiol Exp 2000; 60:531–545
Grewal SS, York RD, Stork PJ. Extracellular-signal-regulated kinase signalling in neurons. Curr Opin Neurobiol 1999; 9:544–553.
Alessandrini A, Namura S, Moskowitz MA, Bonventre JV. MEK1 protein kinase inhibition protects against damage resulting from focal cerebral ischemia. Proc Natl Acad Sci USA 1999; 96:12866–12869.
Grammer TC, Blenis J. Evidence for MEK-independent pathways regulating the prolonged activation of the ERK-MAP kinases. Oncogene 1997; 14:1635–1642.
Hetman M, Kanning K, Cavanaugh JE, Xia Z. Neuroprotection by brain-derived neurotrophic factor is mediated by extracellular signal-regulated kinase and phosphatidylinositol 3-kinase. J Biol Chem 1999; 274:22569–22580.
Gonzalez-Zulueta M, Feldman AB, Klesse LJ, Kalb RG, Dillman JF, Parada LF et al. Requirement for nitric oxide activation of p21(ras)/extracellular regulated kinase in neuronal ischemic preconditioning. Proc Natl Acad Sci USA 2000; 97:436–441.
Ferrer I, Ballabriga J, Pozas E. Transient forebrain ischemia in the adult gerbil is associated with a complex c-Jun response. Neuroreport 1997; 8:2483–2487.
Yang DD, Kuan CY, Whitmarsh AJ, Rincon M, Zheng TS, Davis RJ et al. Absence of excitotoxicity-induced apoptosis in the hippocampus of mice lacking the JNK3 gene. Nature 1997; 389:865–870.
Jeon SH, Kim YS, Bae CD, Park JB. Activation of JNK and p38 in rat hippocampus after kainic acid induced seizure. Exp Mol Med 2000; 32:227–230.
Chihab R, Ferry C, Koziel V, Monin P, Daval JL. Sequential activation of activator protein1-related transcription factors and INK protein kinases may contribute to apoptotic death induced by transient hypoxia in developing brain neurons. Brain Res Mol Brain Res 1998; 63:105–120.
Morishima Y, Gotoh Y, Zieg J, Barrett T, Takano H, Flavell R et al. Beta-amyloid induces neuronal apoptosis via a mechanism that involves the c-Jun N-terminal kinase pathway and the induction of Fas ligand. J Neurosci 2001; 21:7551–7560.
Troy CM, Rabacchi SA, Xu Z, Maroney AC, Connors TJ, Shelanski ML et al. beta-Amyloidinduced neuronal apoptosis requires c-Jun N-terminal kinase activation. J Neurochem 2001; 77:157–164.
Namgung U, Xia Z. Arsenite-induced apoptosis in cortical neurons is mediated by c-Jun N-terminal protein kinase 3 and p38 mitogen-activated protein kinase. J Neurosci 2000; 20:6442–6451.
Herdegen T, Claret FX, Kallunki T, Martin-Villalba A, Winter C, Hunter T et al, Lasting N-terminal phosphorylation of c-Jun and activation of c-Jun N-terminal kinases after neuronal injury. J Neurosci 1998; 18:5124–5135.
Mielke K, Herdegen T. JNK and p38 stresskinases Degenerative effectors of signaltransduction-cascades in the nervous system. Prog Neurobiol 2000; 61:45–60.
Gupta S, Barrett T, Whitmarsh AJ, Cavanagh J, Sluss HK, Derijard B et al. Selective interaction of JNK protein kinase isoforms with transcription factors. Embo J 1996; 15:2760–2770.
Bozyczko-Coyne D, O Kane TM, Wu ZL, Dobrzanski P, Murthy S, Vaught JL et al. CEP1347/KT-7515, an inhibitor of SAPKIJNK pathway activation, promotes survival and blocks multiple events associated with Abeta-induced cortical neuron apoptosis. J Neurochem 2001; 77:849–863.
Zhu X, Raina AK, Rottkamp CA, Aliev G, Perry G, Boux H et al. Activation and redistribution of c-Jun N-terminal kinase/stress activated protein kinase in degenerating neurons in Alzheimer s disease. J Neurochem 2001; 76:435–441.
Saporito MS, Thomas BA, Scott RW. MPTP activates c-Jun NH(2)-terminal kinase (JNK) and its upstream regulatory kinase MKK4 in nigrostriatal neurons in vivo. J Neurochem 2000; 75:1200–1208.
Harding TC, Xue L, Bienemann A, Haywood D, Dickens M, Tolkovsky AM et al. Inhibition of JNK by overexpression of the JNK binding domain of JIP-1 prevents apoptosis in sympathetic neurons. J Biol Chem 2001; 276:4531–4534.
Le-Niculescu H, Bonfoco E, Kasuya Y, Claret FX, Green DR, Karin M Withdrawal of survival factors results in activation of the JNK pathway in neuronal cells leading to Fas ligand induction and cell death. Mol Cell Biol 1999; 19:751–763.
Bruckner SR, Tammariello SP, Kuan CY, Flavell RA, Rakic P, Estus S. JNK3 contributes to c-Jun activation and apoptosis but not oxidative stress in nerve growth factor-deprived sympathetic neurons. J Neurochem 2001; 78:298–303.
Behrens A, Sibilia M, Wagner EF. Amino-terminal phosphorylation of c-Jun regulates stress-induced apoptosis and cellular proliferation. Nat Genet 1999; 21:326–329.
Yang D, Tournier C, Wysk M, Lu HT, Xu J, Davis RJ et al. Targeted disruption of the MKK4 gene causes embryonic death, inhibition of c-Jun NH2-terminal kinase activation, and defects in AP-1 transcriptional activity. Proc Natl Acad Sci USA 1997; 94:3004–3009.
Holland PM, Suzanne M, Campbell JS, Noselli S, Cooper JA. MKK7 is a stress-activated mitogen-activated protein kinase kinase functionally related to hemipterous. J Biol Chem 1997; 272:24994–24998.
Ham J, Eilers A, Whitfield J, Neame SJ, Shah B. c-Jun and the transcriptional control of neuronal apoptosis. Biochem Pharmacol 2000; 60:1015–1021.
Harper SJ, LoGrasso P. Signalling for survival and death in neurones: The role of stress-activated kinases, JNK and p38. Cell Signal 2001; 13:299–310.
Tibbles LA, Ing YL, Kiefer F, Chan J, Iscove N, Woodgett JR et al. MLK-3 activates the SAPK/JNK and p38/RK pathways via SEK1 and MKK3/6. Embo J 1996; 15:7026–7035.
Lin A, Minden A, Martinetto H, Claret FX, Lange-Carter C, Mercurio F et al. Identification of a dual specificity kinase that activates the Jun kinases and p38-Mpk2. Science 1995; 268:286–290.
Ichijo H, Nishida E, Inci K, ten Dijke P, Saitoh M, Moriguchi T et al. Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways. Science 1997; 275:90–94.
Wang XS, Diener K, Jannuzzi D, Trollinger D, Tan TH, Lichenstein H et al. Molecular cloning and characterization of a novel protein kinase with a catalytic domain homologous to mitogen-activated protein kinase kinase kinase. J Biol Chem 1996; 271:31607–31611.
Kanamoto T, Mota M, Takeda K, Rubin LL, Miyazono K, Ichijo H et al. Role of apoptosis signal-regulating kinase in regulation of the c-Jun N-terminal kinase pathway and apoptosis in sympathetic neurons. Mol Cell Biot 2000; 20:196–204.
Whitmarsh AJ, Cavanagh J, Tournier C, Yasuda J, Davis Ri. A mammalian scaffold complex that selectively mediates MAP kinase activation. Science 1998; 281:1671–1674.
Derijard B, Hibi M, Wu IH, Barrett T, Su B, Deng T et al. JNK1: A protein kinase stimulated by UV light and Ha-Ras that binds and phosphorylates the c-Jun activation domain. Cell 1994; 76:1025–1037.
Hu MC, Qiu WR, Wang YP. JNK1, JNK2 and JNK3 are p53 N-terminal serine 34 kinases. Oncogene 1997; 15:2277–2287.
Fuchs SY, Adler V, Pincus MR, Ronai Z. MEKK1/JNK signaling stabilizes and activates p53. Proc Natl Acad Sci USA 1997; 95:10541–10546.
Zhang Y, Zhou L, Miller CA. A splicing variant of a death domain protein that is regulated by a mitogen-activated kinase is a substrate for c-Jun N-terminal kinase in the human central nervous system. Proc Natl Acad Sci USA 1998; 95:2586–2591.
Derijard B, Raingeaud J, Barrett T, Wu IH, Han J, Ulevitch RJ et al. Independent human MAP-kinase signal transduction pathways defined by MEK and MKK isoforms. Science 1995; 267:682–685.
Raingeaud I, Gupta S, Rogers JS, Dickens M, Han J, Ulevitch RJ et al. Pro-inflammatory cytokines and environmental stress cause p38 mitogen-activated protein kinase activation by dual phosphorylation on tyrosine and threonine. J Biol Chem 1995; 270:7420–7426.
Han J, Lee JD, Jiang Y, Li Z, Feng L, Ulevitch RJ. Characterization of the structure and function of a novel MAP kinase kinase (MKK6). J Biol Chem 1996; 271:2886–2891.
Nath R, McGinnis K, Duna S, Shivers B, Wang KK. Inhibition of p38 kinase mimics survival signal-linked protection against apoptosis in rat cerebellar granule neurons. Cell Mol Biol Lett 2001; 6:173–184
Yamagishi S, Yamada M, Ishikawa Y, Matsumoto T, Ikeuchi T, Hatanaka H. p38 mitogenactivated protein kinase regulates low potassium-induced c-Jun phosphorylation and apoptosis in cultured cerebellar granule neurons. J Biol Chem 2001; 276:5129–5133.
Willaime S, Vanhoutte P, Caboche J, Lemaigre-Dubreuil Y, Mariani J, Brugg B. Ceramideinduced apoptosis in cortical neurons is mediated by an increase in p38 phosphorylation and not by the decrease in ERK phosphorylation. Eur J Neurosci 2011; 13:2037–2046.
McLaughlin B, Pal S, Tran MP, Parsons AA, Barone FC, Erhardt JA et al. p38 activation is required upstream of potassium current enhancement and oaspase cleavage in thiol oxidant-induced neuronal apoptosis. J Neurosci 2001; 21:3303–3311.
De Zutter GS, Davis RJ. Pro-apoptotic gene expression mediated by the p38 mitogen-activated protein kinase signal transduction pathway. Proc Natl Acad Sci USA 2001; 98:6168–6173.
Barone FC, Irving EA, Ray AM, Lee JC, Kassis S, Kumar S et al. Inhibition of p38 mitogenactivated protein kinase provides neuroprotection in cerebral focal ischemia. Med Res Rev 2001; 21:129–145.
Kawasaki H, Morooka T, Shimohama S, Kimura J, Hirano T, Gotoh Y et al. Activation and involvement of p38 mitogen-activated protein kinase in glutamate-induced apoptosis in rat cerebellar granule cells. J Biol Chem 1997; 272:18518–18521.
Ghatan S, Larner S, Kinoshita Y, Hetman M, Patel L, Xia Z et al. p38 MAP kinase mediates Bax translocation in nitric oxide-induced apoptosis in neurons. J Cell Biol 2000; 150:335–347.
Cheng A, Chan SL, Milhavet O, Wang S, Mattson MP. p38 MAP kinase mediates nitric oxide-induced apoptosis of neural progenitor cells. J Biol Chem 2001; 276:43320–43327.
Grimes CA, Jope RS. The multifaceted roles of glycogen synthase kinase 3beta in cellular signaling. Prog Neurobiol 2001; 65:391–426.
Cross DA, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 1995; 378:785–789.
Delcommenne M, Tan C, Gray V, Rue L, Woodgett J, Dedhar S. Phosphoinositide-3-OH kinase-dependent regulation of glycogen synthase kinase 3 and protein kinase B/AKT by the integrin-linked kinase. Proc Natl Acad Sci USA 1998; 95:11211–11216.
Spittaels K, Van den Haute C, Van Dorpe J, Geerts H, Mercken M, Bruynseels K et al. Glycogen synthase kinase-3beta phosphorylates protein tau and rescues the axonopathy in the central nervous system of human four-repeat tau transgenic mice. J Biol Chem 2000; 275:41340–41349.
Lucas JJ, Hernandez F, Gomez-Ramos P, Moran MA, Hen R, Avila J. Decreased nuclear beta-catenin, tau hyperphosphorylation and neurodegeneration in GSK-3beta conditional transgenic mice. Embo J 2001; 20:27–39.
Mattson MP. Neuronal death and GSK-3beta: A tau fetish? Trends Neurosci 2001; 24:255–256.
Copani A, Uberti D, Sortino MA, Bruno V, Nicoletti F, Memo M. Activation of cell-cycleassociated proteins in neuronal death: a mandatory or dispensable path? Trends Neurosci 2001; 24:25–31.
Gao CY, Zelenka PS. Induction of cyclin B and H1 kinase activity in apoptotic PC12 cells. Exp Cell Res 1995; 219:612–618.
Timsit S, Rivera S, Ouaghi P, Guischard F, Tremblay E, Ben-Ari Y et al. Increased cyclin D1 in vulnerable neurons in the hippocampus after ischaemia and epilepsy: a modulator of in vivo programmed cell death? Eur J Neurosci 1999; 11:263–278.
Osuga H, Osuga S, Wang F, Fetni R, Hogan MJ, Slack RS et al. Cyclin-dependent kinases as a therapeutic target for stroke. Proc Natl Acad Sci USA 2000; 97:10254–10259.
Giovanni A, Wirtz-Brugger F, Keramaris E, Slack R, Park DS. Involvement of cell cycle elements, cyclin-dependent kinases, pRb, and E2F x DP, in B-amyloid-induced neuronal death. J Biol Chem 1999; 274:19011–19016.
Copani A, Condorelli F, Caruso A, Vancheri C, Sala A, Giuffrida Stella AM et al. Mitotic signaling by beta-amyloid causes neuronal death. Faseb J 1999; 13:2225–2234.
Park DS, Morris EJ, Padmanabhan J, Shelanski ML, Geller HM, Greene LA. Cyclin-dependent kinases participate in death of neurons evoked by DNA- damaging agents. J Cell Biol 1998; 143:457–467.
McShea A, Harris PL, Webster KR, Wahl AF, Smith MA. Abnormal expression of the cell cycle regulators P16 and CDK4 in Alzheimer s disease. Am J Pathol 1997; 150:1933–1939.
Vincent I, Jicha G, Rosado M, Dickson DW. Aberrant expression of mitotic cdc2/cyclin B1 kinase in degenerating neurons of Alzheimer s disease brain. J Neurosci 1997; 17:3588–3598.
Busser J, Geldmacher DS, Herrup K. Ectopic cell cycle proteins predict the sites of neuronal cell death in Alzheimer s disease brain. J Neurosci 1998; 18:2801–2807.
Ding XL, Husseman J, Tomashevski A, Nochlin D, Jin LW, Vincent I: The cell cycle Cdc25A tyrosine phosphatase is activated in degenerating postmitotic neurons in Alzheimer s disease. Am J Pathol 2000; 157:1983–1990.
Maccioni RB, Otth C, Concha, II, Munoz JP. The protein kinase Cdk5. Structural aspects, roles in neurogenesis and involvement in Alzheimer s pathology. Eur J Biochem 2001; 268:1518–1527.
Vincent I, Bu B, Hudson K, Husseman J, Nochlin D, Jin L. Constitutive Cdc25B tyrosine phosphatase activity in adult brain neurons with M phase-type alterations in Alzheimer s disease. Neuroscience 2001; 105:639–650
Patrick GN, Zukerberg L, Nikolic M, de la Monte S, Dikkes P, Tsai LH. Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration. Nature 1999; 402:615–622.
Nguyen MD, Lariviere RC, Julien JP. Deregulation of Cdk5 in a mouse model of ALS: Toxicity alleviated by perikaryal neurofilament inclusions. Neuron 2001; 30:135–147.
Park DS, Levine B, Ferrari G, Greene LA. Cyclin dependent kinase inhibitors and dominant negative cyclin dependent kinase 4 and 6 promote survival of NGF-deprived sympathetic neurons. J Neurosci 1997; 17:8975–8983.
Padmanabhan J, Park DS, Greene LA, Shelanski ML. Role of cell cycle regulatory proteins in cerebellar granule neuron apoptosis. J Neurosci 1999; 19:8747–8756.
Park DS, Morris EJ, Greene LA, Geller HM. G1/S cell cycle blockers and inhibitors of cyclin-dependent kinases suppress camptothecin-induced neuronal apoptosis. J Neurosci 1997; 17:1256–1270.
Morris EJ, Keramaris E, Rideout HJ, Slack RS, Dyson NJ, Stefanis L et al. Cyclin-dependent kinases and P53 pathways are activated independently and mediate Bax activation in neurons after DNA damage. J Neurosci 2001; 21:5017–5026.
Park DS, Morris EJ, Stefanis L, Troy CM, Shelanski ML, Geller HM. Multiple pathways of neuronal death induced by DNA-damaging agents, NGF deprivation, and oxidative stress. J Neurosci 1998; 18:830–840.
Van den Haute C, Spittaels K, Van Dorpe J, Lacrado R, Vandezande K, Laenen I et al. Coexpression of human cdk5 and its activator p35 with human protein tau in neurons in brain of triple transgenic mice. Neurobiol Dis 2001; 8:32–44.
Kesavapany S, Lau KF, McLoughlin DM, Brownlees J, Ackerley S, Leigh PN et al. p35/ cdk5 binds and phosphorylates beta-catenin and regulates beta-catenin/presenilin-1 interaction. Eur J Neurosci 2001; 13:241–247.
Hou ST, Callaghan D, Fournier MC, Hill I, Kang L, Massie B et al. The transcription factor E2F1 modulates apoptosis of neurons. J Neurochem 2000; 75:91–100.
Hare MJ, Hou ST, Morris EJ, Cregan SP, Xu Q, Slack RS et al. Induction and modulation of cerebellar granule neuron death by E2F-l. J Biol Chem 2000; 275:25358–25364.
Smith DS, Leone G, DeGregori J, Ahmed MN, Qumsiyeh MB, Nevins JR. Induction of DNA replication in adult rat neurons by deregulation of the retinoblastoma/E2F G1 cell cycle pathway. Cell Growth Differ 2000; 11:625–633.
Park DS, Morris EJ, Bremner R, Keramaris E, Padmanabhan J, Rosenbaum M et al. Involvement of retinoblastoma family members and E2F/DP complexes in the death of neurons evoked by DNA damage. J Neurosci 2000; 20:3104–3114.
MacManus JP, Koch CJ, Jian M, Walker T, Zurakowski B. Decreased brain infarct following focal ischemia in mice lacking the transcription factor E2FI. Neuroreport 1999; 10:2711–2714.
Gendron TF, Mealing GA, Paris J, Lou A, Edwards A, Hou ST et al. Attenuation of neurotoxicity in cortical cultures and hippocampal slices from E2F1 knockout mice. J Neurochem 2001; 78:316–324..
Giovanni A, Keramaris E, Morris EJ, Hou ST, O Hare M, Dyson N et al. E2F1 mediates death of B-amyloid-treated cortical neurons in a manner independent of p53 and dependent on Bax and caspase 3. J Biol Chem 2000; 275:11553–11560.
Tamami M, Lindholm PF, Brady JN. The retinoblastoma gene product (Rb) induces binding of a conformationally inactive nuclear factor-kappaB. J Biol Chem 1996; 271:24551–24556.
Shim J, Park HS, Kim MJ, Park J, Park E, Cho SG et al. Rb protein down-regulates the stress-activated signals through inhibiting c-Jun N-terminal kinase/stress-activated protein kinase. J Biol Chem 2000; 275:14107–14111.
Jordan J, Galindo MF, Prehn JH, Weichselbaum RR, Beckett M, Ghadge GD et al. p53 expression induces apoptosis in hippocampal pyramidal neuron cultures. J Neurosci 1997; 17:1397–1405.
Macleod KF, Hu Y, Jacks T. Loss of Rb activates both p53-dependent and independent cell death pathways in the developing mouse nervous system. Embo J 1996; 15:6178–6188.
Lipinski MM, Macleod KF, Williams BO, Mullaney TL, Crowley D, Jacks T. Cell-autonomous and non-cell-autonomous functions of the Rb tumor suppressor in developing central nervous system. Embo J 2001; 20:3402–3413.
Nip J, Strom DK, Eischen CM, Cleveland JL, Zambetti GP, Hiebert SW. E2F-1 induces the stabilization of p53 but blocks p53-mediated transactivation. Oncogene 2001; 20:910–920.
Ko LJ, Prives C. p53: Puzzle and paradigm. Genes Dev 1996; 10:1054–1072.
Giaccia AJ, Kastan MB. The complexity of p53 modulation: Emerging patterns from divergent signals. Genes Dev 1998; 12:2973–2983.
Bates S, Vousden KH. p53 in signaling checkpoint arrest or apoptosis. Curr Opin Genet Dev 1996; 6:12–18.’
Asker C, Wiman KG, Selivanova G. p53-induced apoptosis as a safeguard against cancer. Biochem Biophys Res Commun 1999; 265:1–6.
Miyashita T, Harigai M, Hanada M, Reed JC. Identification of a p53-dependent negative response element in the bc1–2 gene. Cancer Res 1994; 54:3131–3135.
Roperch JP, Alvaro V, Prieur S, Tuynder M, Nemani M, Lethrosne F et al. Inhibition of presenilin 1 expression is promoted by p53 and p21WAF-1 and results in apoptosis and tumor suppression. Nat Med 1998; 4:835–838.
Ding HF, McGill G, Rowan S, Schmaltz C, Shimamura A, Fisher DE. Oncogene-dependent regulation of caspase activation by p53 protein in a cell-free system. J Biol Chem 273: 28378–28383.
Gottlieb E, and Oren M (1998) p53 facilitates pRb cleavage in IL-3-deprived cells: Novel pro-apoptotic activity of p53. Embo J 1998; 17:3587–3596.
Morrison RS, Kinoshita Y. The role of p53 in neuronal cell death. Cell Death Differ 2000; 7:868–879.
Sakhi S, Bruce A, Sun N, Tocco G, Baudry M, Schreiber SS. p53 induction is associated with neuronal damage in the central nervous system. Proc Natl Acad Sci USA 1994; 91:7525–7529.
Sakhi S, Sun N, Wing LL, Mehta P, Schreiber SS. Nuclear accumulation of p53 protein following kainic acid-induced seizures. Neuroreport 1996; 7:493–496.
Nakai M, Qin ZH, Chen JF, Wang Y, Chase TN. Kainic acid-induced apoptosis in rat striatum is associated with nuclear factor-kappaB activation. J Neurochem 2000; 74:647–658.
Qin ZH, Chen RW, Wang Y, Nakai M, Chuang DM, Chase TN. Nuclear factor kappaB nuclear translocation upregulates c-Myc and p53 expression during NMDA receptor-mediated apoptosis in rat striatum, J Neurosci 1999; 19:4023–4033.
Wang Y, Qin ZH, Nakai M, Chen RW, Chuang DM, Chase TN. Co-stimulation of cyclicAMP-linked metabotropic glutamate receptors in rat striatum attenuates excitotoxin-induced ’ nuclear factor-kappaB activation and apoptosis. Neuroscience 1999; 94:1153–1162.
Napieralski JA, Raghupathi R, McIntosh TK. The tumor-suppressor gene, p53, is induced in injured brain regions following experimental traumatic brain injury. Brain Res Mol Brain Res 1999; 71:78–86.
Lu J, Moochhala S, Kaur C, Ling E. Changes in apoptosis-related protein (p53, Bax, Bcl-2 and Fos) expression with DNA fragmentation in the central nervous system in rats after closed head injury. Neurosci Lett 2000; 290:89–92.
Martin LI, Kaiser A, Yu JW, Natale JE, Al-Abdulla NA. Injury-induced apoptosis of neurons in adult brain is mediated by p53-dependent and p53-independent pathways and requires Bax. J Comp Neurol 2001; 433:299–311.
Chopp M, Li Y, Zhang ZG, Freytag SO. p53 expression in brain after middle cerebral artery occlusion in the rat. Biochem Biophys Res Commun 1992; 182:1201–1207.
Watanabe H, Ohta S, Kumon Y, Sakaki S, Sakanaka M. Increase in p53 protein expression following cortical infarction in the spontaneously hypertensive rat. Brain Res 1999; 837:38–45.
de la Monte SM, Sohn YK, Wands JR. Correlates of p53- and Fas (CD95)-mediated apoptosis in Alzheimer s disease. J Neurol Sci 1997; 152:73–83.
de la Monte SM, Sohn YK, Ganju N, Wands JR. P53- and CD95-associated apoptosis in neurodegenerative diseases. Lab Invest 1998; 78:401–411.
LaFerla FM, Hall CK, Ngo L, Jay G. Extracellular deposition of beta-amyloid upon p53-dependent neuronal cell death in transgenic mice. J Clin Invest 1996; 98:1626–1632.
Jiang YH, Armstrong D, Albrecht U, Atkins CM, Noebels JL, EicheleGet al. Mutation of the Angelman ubiquitin ligase in mice causes increased cytoplasmic p53 and deficits of contextual learning and long-term potentiation [see comments]. Neuron 1998; 21:799–811.
Sawa A. Neuronal cell death in Down s syndrome. J Neural Transm Suppl 1999; 57:87–97.
Seidl R, Fang-Kircher S, Bidmon B, Cairns N, Lubec G. Apoptosis-associated proteins p53 and APO-1/Fas (CD95) in brains of adult patients with Down syndrome. Neurosci Lett 1999; 260:9–12.
Martin Li. p53 is abnormally elevated and active in the CNS of patients with amyotrophic lateral sclerosis. Neurobiol Dis 2000; 7:613–622.
Steffan JS, Kazantsev A, Spasic-Boskovic O, Greenwald M, Zhu YZ, Gohler H et al. The Huntington s disease protein interacts with p53 and CREB-binding protein and represses transcription. Proc Natl Acad Sci USA 2000; 97:6763–6768.
Uberti D, Belloni M, Grilli M, Span P, Memo M. Induction of tumour-suppressor phosphoprotein p53 in the apoptosis of cultured rat cerebellar neurones triggered by excitatory amino acids. Eur J Neurosci 1998; 10:246–254.
Chen RW, Chuang DM. Long term lithium treatment suppresses p53 and Bax expression but increases BcI-2 expression. A prominent role in neuroprotection against excitotoxicity. J Biol Chem 1999; 274:6039–6042.
Anderson CNG, Tolkovsky AM. A role for MAPK/ERK in sympathetic neuron survival: Protection against a p53-dependent, JNK-independent induction of apoptosis by cytosine arabinoside. J Neurosci 1999; 19:664–673.
Chen RW, Saunders PA, Wei H, Li Z, Seth P, Chuang DM. Involvement of glyceraldehyde3-phosphate dehydrogenase (GAPDH) and p53 in neuronal apoptosis: evidence that GAPDH is upregulated by p53. J Neurosci 1999; 19:9654–9662.
Frank KM, Sharpless NE, Gao Y, Sekiguchi JM, Ferguson DO, Zhu C et al. DNA ligase IV deficiency in mice leads to defective neurogenesis and embryonic lethality via the p53 pathway. Mol Cell 2000; 5:993–1002.
Banasiak KJ, Haddad GG. Hypoxia-induced apoptosis: Effect of hypoxic severity and role of p53 in neuronal cell death. Brain Res 1998; 797:295–304.
Crumrine RC, Thomas AL, Morgan PF. Attenuation of p53 expression protects against focal ischemic damage in transgenic mice. J Cereb Blood Flow Metab 1994; 14:887–891.
Johnson MD, Xiang H, London S, Kinoshita Y, Knudson M, Mayberg M et al. Evidence for involvement of Bax and p53, but not caspases, in radiation-induced cell death of cultured postnatal hippocampal neurons. J Neurosci Res 1998; 54:721–733.
Wood KA, Youle RJ. The role of free radicals and p53 in neuron apoptosis in vivo. J Neurosci 1995; 15:5851–5857.
Enokido Y, Araki T, Tanaka K, Aizawa S, Hatanaka H. Involvement of p53 in DNA strand break-induced apoptosis in postmitotic CNS neurons. Eur J Neurosci 1996; 8:1812–1821.
D Sa-Eipper C, Leonard JR, Putcha G, Zheng TS, Flavell RA, Rakic P et al. DNA damage-induced neural precursor cell apoptosis requires p53 and caspase 9 but neither Bax nor caspase 3. Development 2001; 128:137–146.
Herzog KH, Chong MJ, Kapsetaki M, Morgan JI, McKinnon PJ. Requirement for Atm in ionizing radiation-induced cell death in the developing central nervous system. Science 1998; 280:1089–1091.
Morrison RS, Wenzel HJ, Kinoshita Y, Robbins CA, Donehower LA, Schwartzkroin PA. Loss of the p53 tumor suppressor gene protects neurons from kainate-induced cell death. J Neurosci 1996; 16:1337–1345.
Trimmer PA, Smith TS, Jung AB, Bennett JP, Jr. Dopamine neurons from transgenic mice with a knockout of the p53 gene resist MPTP neurotoxicity. Neurodegeneration 1996; 5:233–239.
Hirata H, Cadet JL. p53-knockout mice are protected against the long-term effects of meth-amphetamine on dopaminergic terminals and cell bodies. J Neurochem 1997; 69:780–790.
Sakhi S, Gilmore W, Tran ND, Schreiber SS. p53-deficient mice are protected against adrenalectomy-induced apoptosis. Neuroreport 1996; 8:233–235.
Enokido Y, Araki T, Aizawa S, Hatanaka H. p53 involves cytosine arabinoside-induced apoptosis in cultured cerebellar granule neurons. Neurosci Lett 1996; 203:1–4.
Araki T, Enokido Y, Inamura N, Aizawa S, Reed JC, Hatanaka H. Changes in c-Jun but not Bcl-2 family proteins in p53-dependent apoptosis of mouse cerebellar granule neurons induced by DNA damaging agent bleomycin. Brain Res 1998; 794:239–247.
Xiang H, Kinoshita Y, Knudson CM, Korsmeyer SJ, Schwartzkroin PA, Morrison RS. Bax involvement in p53-mediated neuronal cell death. J Neurosci 1998; 18:1363–1373.
Halterman MW, Miller CC, FederoffHJ. Hypoxia-inducible factor-1 alpha mediates hypoxiainduced delayed neuronal death that involves p53. J Neurosci 1999; 19:6818–6824.
Aloyz RS, Bamji SX, Pozniak CD, Toma JG, Atwal J, Kaplan DR et al. p53 is essential for developmental neuron death as regulated by the TrkA and p75 neurotrophin receptors. J Cell Biol 1998; 143:1691–1703.
Vogel KS, Parada LF. Sympathetic neuron survival and proliferation are prolonged by loss of p53 and neurofibromin. Mol Cell Neurosci 1998; 11:19–28.
Lee EY, Chang CY, Hu N, Wang YC, Lai CC, Herrup K et al. Mice deficient for Rb are nonviable and show defects in neurogenesis and haematopoiesis [see comments]. Nature 1992; 359:288–294.
Yeung MC, Geertsma F, Liu J, Lau AS. Inhibition of HIV-1 gp120-induced apoptosis in neuroblastoma SK-N-SH cells by an antisense oligodeoxynucleotide against p53. AIDS 1998; 12:349–354.
Lakkaraju A, Dubinsky JM, Low WC, Rahman YE. Neurons are protected from excitotoxic death by p53 antisense oligonucleotides delivered in anionic liposomes. J Biol Chem 2001; 276:32000–32007.
Culmsee C, Zhu X, Yu QS, Chan SL, Camandola S, Guo Z et al. A synthetic inhibitor of p53 protects neurons against death induced by ischemic and excitotoxic insults, and amyloid beta-peptide. J Neurochem 2001; 77:220–228.
Kuntz C, Kinoshita Y, Beal F, Donehower LA, Morrison RS. The absence of p53 does not protect SOD1 mutant mice from onset of clincial symptoms or lethality. Exp Neurol 2000; 165:184–190.
Prudlo J, Koenig J, Graser J, Burckhardt E, Mestres P, Menger M et al. Motor neuron cell death in a mouse model of FALS is not mediated by the p53 cell survival regulator. Brain Res 2000; 879:183–187.
Chong MJ, Murray MR, Gosink EC, Russell HR, Srinivasan A, Kapsetaki M et al. Atm and Bax cooperate in ionizing radiation-induced apoptosis in the central nervous system. Proc Natl Acad Sci USA 2000; 97:889–894.
Cregan SP, MacLaurin JG, Craig CG, Robertson GS, Nicholson DW, Park DS et al. Baxdependent caspase-3 activation is a key determinant in p53-induced apoptosis in neurons. J Neurosci 1999; 19:7860–7869.
McGinnis KM, Gnegy ME, Wang KK. Endogenous Bax translocation in SH-SY5Y human neuroblastoma cells and cerebellar granule neurons undergoing apoptosis. J Neurochem 1999; 72:1899–1906.
Putcha GV, Deshmukh M, Johnson EM, Jr. BAX translocation is a critical event in neuronal apoptosis: regulation by neuroprotectants, BCL-2, and caspases. J Neurosci 1999; 19:7476–7485.
Xiang J, Chao DT, Korsmeyer SJ. BAX-induced cell death may not require interleukin 1 beta-converting enzyme-like proteases. Proc Natl Acad Sci USA 1996; 93:14559–14563.
Vekrellis K, McCarthy M7, Watson A, Whitfield J, Rubin LL, Ham J. Bax promotes neuronal cell death and is downregulated during the development of the nervous system. Development 1997; 124:1239–1249.
Martinou I, Missotten M, Fernandez PA, Sadoul R, Martinou JC. Bax and Bak proteins require caspase activity to trigger apoptosis in sympathetic neurons. Neuroreport 1998; 9:15–19.
Marzo I, Brenner C, Zamzami N, Jurgensmeier JM, Susin SA, Vieira HL et al. Bax and adenine nucleotide translocator cooperate in the mitochondrial control of apoptosis. Science 1998; 281:2027–2031.
Schuler M, Bossy-Wetzel E, Goldstein JC, Fitzgerald P, Green DR. p53 induces apoptosis by caspase activation through mitochondrial cytochrome c release. J Biol Chem 2000; 275:7337–7342.
Johnson MD, Kinoshita Y, Xiang H, Ghatan S, Morrison RS. Contribution of p53-dependent caspase activation to neuronal cell death declines with neuronal maturation. J Neurosci 1999; 19:2996–3006.
Fortin A, Cregan SP, MacLaurin JG, Kushwaha N, Hickman ES, Thompson CS et al. APAF1 is a key transcriptional target for p53 in the regulation of neuronal cell death. J Cell Biol 2001; 155:207–216.
Attardi LD, Reczek EE, Cosmas C, Demicco EG, McCurrach ME, Lowe SW et al. PERP, an apoptosis-associated target of p53, is a novel member of the PMP-22/gas3 family [In Process Citation]. Genes Dev 2000; 14:704–718.
Ferri KF, Kroemer G. Organelle-specific initiation of cell death pathways. Nat Cell Biol 2001; 3:E255–263.
Lewen A, Matz P, Chan PH. Free radical pathways in CNS injury. J Neurotrauma 2000; 17:871–890.
Mattson MP. Apoptosis in neurodegenerative disorders. Nat Rev Mol Cell Biol 2000; 1:120–129.
Tong X, Liu B, Dong Y, Sun Z. Cleavage of ATM during radiation-induced apoptosis: Caspase-3-like apoptotic protease as a candidate. Int J Radiat Biol 2000; 76:1387–1395.
Song Q, Lees-Miller SP, Kumar S, Zhang Z, Chan DW, Smith GC et al. DNA-dependent protein kinase catalytic subunit: A target for an ICE- like protease in apoptosis. Embo J 1996; 15:3238–3246.
Han Z, Malik N, Carter T, Reeves WIT, Wyche JH, Hendrickson EA. DNA-dependent protein kinase is a target for a CPP32-like apoptotic protease. J Biol Chem 1996; 271:25035–25040.
Tewari M, Quan LT, O Rourke K, Desnoyers S, Zeng Z, Beidler DR et al. Yama/CPP32 beta, a mammalian homolog of CED-3, is a CrmA-inhibitable protease that cleaves the death substrate poly(ADP-ribose) polymerase. Cell 1995; 81:801–809.
Lazebnik YA, Kaufmann SH, Desnoyers S, Poirier GG, Earnshaw WC. Cleavage of poly(ADP-ribose) polymerase by a proteinase with properties like ICE. Nature 1994; 371:346–347.
Kastan MB, Lim DS. The many substrates and functions of ATM. Nat Rev Mol Cell Biol 2000; 1:179–186.
Barlow C, Hirotsune S, Paylor R, Liyanage M, Eckhaus M, Collins F et al. Atm-deficient mice: A paradigm of ataxia telangiectasia. Cell 1996; 86:159–171.
Canman CE, Lim DS, Cimprich KA, Taya Y, Tamai K, Sakaguchi K et al. Activation of the ATM kinase by ionizing radiation and phosphorylation of p53. Science 1998; 281:1677–1679.
Banin S, Moyal L, Shieh S, Taya Y, Anderson CW, Chessa L et al. Enhanced phosphorylation of p53 by ATM in response to DNA damage. Science 1998; 281:1674–1677.
Caspari T. How to activate p53. Curr Biol 2000; 10:R315–317.
Khosravi R, Maya R, Gottlieb T, Oren M, Shiloh Y, Shkedy D. Rapid ATM-dependent phosphorylation of MDM2 precedes p53 accumulation in response to DNA damage. Proc Natl Acad Sci USA 1999; 96:14973–14977.
Maya R, Balass M, Kim ST, Shkedy D, Leal JF, Shifman O et al. ATM-dependent phosphorylation of Mdm2 on serine 395: Role in p53 activation by DNA damage. Genes Dev 2001; 15:1067–1077.
Meek DW. Mechanisms of switching on p53: A role for covalent modification? Oncogene 1999; 18:7666–7675.
Lee Y, Chong MJ, McKinnon PJ. Ataxia telangiectasia mutated-dependent apoptosis after genotoxic stress in the developing nervous system is determined by cellular differentiation status. J Neurosci 2001; 21:6687–6693.
Rolig RL, McKinnon PJ. Linking DNA damage and neurodegeneration. Trends Neurosci 2000; 23:417–424.
Shiloh Y. ATM and ATR: networking cellular responses to DNA damage. Curr Opin Genet Dev 2001; 11:71–77.
Hammarsten O, DeFazio LG, Chu G. Activation of DNA-dependent protein kinase by single-stranded DNA ends. J Biol Chem 2000; 275:1541–1550.
Smith GC, Jackson SP. The DNA-dependent protein kinase. Genes Dev 1999; 13:916–934.
Lees-Miller SP, Sakaguchi K, Ullrich SJ, Appella E, Anderson CW. Human DNA-activated protein kinase phosphorylates serines 15 and 37 in the amino-terminal transactivation domain of human p53. Mol Cell Biol 1992; 12:5041–5049.
Mayo LD, Turchi JJ, Berberich SJ. Mdm-2 phosphorylation by DNA-dependent protein kinase prevents interaction with p53. Cancer Res 1997; 57:5013–5016.
Kharbanda S, Yuan ZM, Weichselbaum R, Kufe D. Determination of cell fate by c-Abl activation in the response to DNA damage. Oncogene 1998; 17:3309–3318.
Liu L, Kwak YT, Bex F, Garcia-Martinez LF, Li XH, Meek K et al. DNA-dependent protein kinase phosphorylation of IkappaB alpha and IkappaB beta regulates NF-kappaB DNA binding properties. Mol Cell Biol 1998; 18:4221–4234.
ChechlacZ M, Vemuri MC, Naegele JR. Role of DNA-dependent protein kinase in neuronal survival. J Neurochem 2001; 78:141–154.
Vemuri MC, Schiller E, Naegele JR. Elevated DNA double strand breaks and apoptosis in the CNS of seid mutant mice. Cell Death Differ 2001; 8:245–255.
Culmsee C, Bondada S, Mattson MP. Hippocampal neurons of mice deficient in DNA-dependent protein kinase exhibit increased vulnerability to DNA damage, oxidative stress and excitotoxicity. Brain Res Mol Brain Res 2001; 87:257–262.
Chakravarthy BR, Walker T, Rasquinha I, Hill IE, MacManus JP. Activation of DNA-dependent protein kinase may play a role in apoptosis of human neuroblastoma cells. J Neurochem 1999; 72:933–942.
Smith S. The world according to PARP. Trends Biochem Sci 2001; 26:174–179.
Herceg Z, Wang ZQ. Functions of poly(ADP-ribose) polymerase (PARP) in DNA repair, genomic integrity and cell death. Mutat Res 2001; 477:97–110.
Le Rhun Y, Kirkland JB, Shah GM. Cellular responses to DNA damage in the absence of Poly(ADP-ribose) polymerase. Biochem Biophys Res Commun 1998; 245:1–10.
Ziegler M, Oei SL. A cellular survival switch: Poly(ADP-ribosyl)ation stimulates DNA repair and silences transcription. Bioessays 2001; 23:543–548.
Ha HC, Snyder SH. Poly(ADP-ribose) polymerase is a mediator of necrotic cell death by ATP depletion. Proc Natl Acad Sci USA 1999; 96:13978–13982.
Ha HC, Snyder SH. Poly(ADP-ribose) polymerase-1 in the nervous system. Neurobiol Dis 2000; 7:225–239.
Cosi C, Suzuki H, Milani D, Facci L, Menegazzi M, Vantini G et al. Poly(ADP-ribose) polymerase: early involvement in glutamate-induced neurotoxicity in cultured cerebellar granule cells. J Neurosci Res 1994; 39:38–46.
Zhang J, Dawson VL, Dawson TM, Snyder SH. Nitric oxide activation of poly(ADP-ribose) synthetase in neurotoxicity. Science 1994; 263:687–689.
Eliasson MJ, Sampei K, Mandir AS, Hurn PD, Traystman RJ, Bao J et al. Poly(ADP-ribose) polymerase gene disruption renders mice resistant to cerebral ischemia. Nat Med 1997; 3:1089–1095.
Endres M, Wang ZQ, Namura S, Waeber C, Moskowitz MA. Ischemic brain injury is mediated by the activation of poly(ADP- ribose)polymerase. J Cereb Blood Flow Metab 1997; 17:1143–1151.
Mandir AS, Poitras MF, Berliner AR, Herring WJ, Guastella DB, Feldman A et al. NMDA but not non-NMDA excitotoxicity is mediated by Poly(ADP-ribose) polymerase. J Neurosci 2000; 20:8005–8011.
Mandir AS, Przedborski S, Jackson-Lewis V, Wang ZQ, Simbulan-Rosenthal CM, Smulson ME et al. Poly(ADP-ribose) polymerase activation mediates 1-methyl-4-phenyl-1, 2,3,6tetrahydropyridine (MPTP)-induced parkinsonism. Proc Natl Acad Sci USA 1999; 96:5774–5779.
Ding Y, Zhou Y, Lai Q, Li J, Gordon V, Diaz FG. Long-term neuroprotective effect of inhibiting poly(ADP-ribose) polymerase in rats with middle cerebral artery occlusion using a behavioral assessment. Brain Res 2001; 915:210–217.
Whalen MJ, Clark RS, Dixon CE, Robichaud P, Marion DW, Vagni V et al. Traumatic brain injury in mice deficient in poly-ADP(ribose) polymerase: A preliminary report. Acta Neurochir Suppl 2000; 76:61–64
Moroni F, Meli E, Peruginelli F, Chiarugi A, Cozzi A, Picca R et al. Poly(ADP-ribose) polymerase inhibitors attenuate necrotic but not apoptotic neuronal death in experimental models of cerebral ischemia. Cell Death Differ 2001; 8:921–932.
Kruman, II, Culmsee C, Chan SL, Kruman Y, Guo Z, Penix L et al. Homocysteine elicits a DNA damage response in neurons that promotes apoptosis and hypersensitivity to excitotoxicity. J Neurosci 2000; 20:6920–6926.
Yang E, Korsmeyer SJ. Molecular thanatopsis: A discourse on the BCL2 family and cell death. Blood 1996; 88:386–401.
Bakhshi A, Jensen JP, Goldman P, Wright JJ, McBride OW, Epstein AL et al. Cloning the chromosomal breakpoint of t(14;18) human lymphomas: Clustering around JH on chromosome 14 and near a transcriptional unit on 18. Cell 1985; 41:899–906.
Cleary ML, Smith SD, Sklar J. Cloning and structural analysis of cDNAs for bc1–2 and a hybrid bcl- 2/immunoglobulin transcript resulting from the t(14;18) translocation. 1986; Cell 47:19–28.
Tsujimoto Y, Finger LR, Yunis J, Nowell PC, Croce CM. Cloning of the chromosome breakpoint of neoplastic B cells with the t(14;18) chromosome translocation. Science 1984; 226:1097–1099.
Huang DC, Strasser A. BH3-Only proteins-essential initiators of apoptotic cell death. Cell 2000; 103:839–842.
Oda E, Ohki R, Murasawa H, Nemoto J, Shibue T, Yamashita T et al. Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis. Science 2000; 288:1053–1058.
Nechushtan A, Smith CL, Lamensdorf I, Yoon SH, Youle RJ. Bax and Bak coalesce into novel mitochondria-associated clusters during apoptosis. J Cell Biol 2001; 153:1265–1276.
Hsu YT, Wolter KG, Youle RJ. Cytosol-to-membrane redistribution of Bax and Bc1-X(L) during apoptosis. Proc Natl Acad Sei USA 1997; 94:3668–3672.
Wolter KG, Hsu YT, Smith CL, Nechushtan A, Xi XG et al. Movement of Bax from the cytosol to mitochondria during apoptosis. J Cell Biol 1997; 139:1281–1292.
Zha H, Fisk HA, Yaffe MP, Mahajan N, Herman B, Reed JC. Structure-function comparisons of the proapoptotic protein Bax in yeast and mammalian cells. Mol Cell Biol 1996; 16:6494–6508.
Thornberry NA, Lazebnik Y. Caspases: Enemies within. Science 1998; 281:1312–1316.
Green DR, Reed JC. Mitochondria and apoptosis. Science 1998; 281:1309–1312.
Kluck RM, Bossy-Wetzel E, Green DR, Newmeyer DD. The release of cytochrome c from mitochondria: A primary site for Bc1–2 regulation of apoptosis. Science 1997; 275:1132–1136.
Yang J, Liu X, Bhalla K, Kim CN, Ibrado AM, Cai J, Peng TI, Jones DP, and Wang X (1997) Prevention of apoptosis by Bc1–2: release of cytochrome c from mitochondria blocked. Science 275: 1129–1132.
Harris MH, Thompson CB. The role of the Bcl-2 family in the regulation of outer mitochondrial membrane permeability. Cell Death Differ 2000; 7:1182–1191.
Kowaltowski AJ, Smaili SS, Russell JT, Fiskum G. Elevation of resting mitochondrial membrane potential of neural cells by cyclosporin A, BAPTA-AM, and bcl-2. Am J Physiol Cell Physiol 2000; 279:C852–859.
Schendel SL, Manta] M, Reed JC. Bcl-2 family proteins as ion-channels. Cell Death Differ 1998; 5:372–380.
Saito M, Korsmeyer SJ, Schlesinger PH. BAX-dependent transport of cytochrome c reconstituted in pure liposomes. Nat Cell Biol 2000; 2:553–555.
Martinou JC, Green DR. Breaking the mitochondria(barrier. Nat Rev Mol Cell Biol 2001; 2:63–67.
Gross A, Jockel J, Wei MC, Korsmeyer SJ. Enforced dimerization of BAX results in its translocation, mitochondrial dysfunction and apoptosis. Embo J 1998; 17:3878–3885.
Oltvai ZN, Milliman CL, Korsmeyer SJ. Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell 1993; 74:609–619.
Yin XM, Oltvai ZN, Korsmeyer SI. BH1 and BH2 domains of Bel-2 are required for inhibition of apoptosis and heterodimerization with Bax. Nature 1994; 369:321–323.
Sattler M, Liang H, Nettesheim D, Meadows RP, Harlan JE, Eberstadt M et al. Structure of Bcl-xL-Bak peptide complex: recognition between regulators of apoptosis. Science 1997; 275:983–986.
Muchmore SW, Sattler M, Liang H, Meadows RP, Harlan JE, Yoon HS et al. X-ray and NMR structure of human Bcl-xL, an inhibitor of programmed cell death. Nature 1996; 381:335–341.
Wang K, Yin XM, Chao DT, Milliman CL, Korsmeyer S.1. BID: A novel BH3 domain-only death agonist. Genes Dev 1996; 10:2859–2869.
Zha J, Harada H, Osipov K, Jockel J, Waksman G, Korsmeyer SJ. BH3 domain of BAD is required for heterodimerization with BCL-XL and pro-apoptotic activity. J Biol Chem 1997; 272:24101–24104.
Zha J, Harada H, Yang E, Jockel J, Korsmeyer SJ. Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14–3–3 not BCL-X(L). Cell 1996; 87:619–628.
Blagosklonny MV. Unwinding the loop of Bc1–2 phosphorylation. Leukemia 2001; 15:869–874.
Ruvolo PP, Deng X, May WS. Phosphorylation of Bc12 and regulation of apoptosis. Leukemia 2001; 15:515–522.
Wei MC, Lindsten T, Mootha VK, Weiler S, Gross A, Ashiya M et al. tBID, a membrane-targeted death ligand, oligomerizes BAK to release cytochrome c. Genes Dev 2000; 14:2060–2071.
Fesik SW. Insights into programmed cell death through structural biology. Cell 2000; 103:273–282.
Lutter M, Fang M, Luo X, Nishijima M, Xie X, Wang X. Cardiolipin provides specificity for targeting of tBid to mitochondria. Nat Cell Biol 2000; 2:754–761.
Korsmeyer SJ, Wei MC, Saito M, Weiler S, Oh KJ, Schlesinger PH. Pro-apoptotic cascade activates BID, which oligomerizes BAK or BAX into pores that result in the release of cytochrome c. Cell Death Differ 2000; 7:1166–1173.
Wei MC, Zong WX, Cheng EH, Lindsten T, Panoutsakopoulou V, Ross AJ et al. Proapoptotic BAX and BAK: A requisite gateway to mitochondrial dysfunction and death. Science 2001; 292:727–730.
Desagher S, Osen-Sand A, Nichols A, Eskes R, Montessuit S, Lauper S et al. Bid-induced conformational change of Bax is responsible for mitochondria] cytochrome c release during apoptosis. J Cell Biol 1999; 144:891–901.
Connor L, Strasser A, O Reilly LA, Hausmann G, Adams JM, Cory S et al. Bim: A novel member of the Bel-2 family that promotes apoptosis. Embo J 1998; 17:384–395.
Ottilie S, Diaz JL, Horne W, Chang J, Wang Y, Wilson G et al. Dimerization properties of human BAD. Identification of a BH-3 domain and analysis of its binding to mutant BCL-2 and BCL-XL proteins. J Biol Chem 1997; 272:30866–30872.
Merry DE, Korsmeyer SJ. Bel-2 gene family in the nervous system. Annu Rev Neurosci 1997; 20:245–267
Oppenheim RW. Cell death during development of the nervous system. Annu Rev Neurosci 1991; 14:453–501
Sadoul R. Bel-2 family members in the development and degenerative pathologies of the nervous system. Cell Death Differ 1998; 5:805–815.
Ay I, Sugimori H, Finklestein SP. Intravenous basic fibroblast growth factor (bFGF) decreases DNA fragmentation and prevents downregulation of Bc1–2 expression in the ischemic brain following middle cerebral artery occlusion in rats. Brain Res Mol Brain Res 2001; 87:71–80.
Miller TM, Moulder KL, Knudson CM, Creedon DJ, Deshmukh M, Korsmeyer SJ et al. Bax deletion further orders the cell death pathway in cerebellar granule cells and suggests a caspase-independent pathway to cell death. J Cell Biol 1997; 139:205–217.
En KL, Graham SB, Mao XO, He X, Nagayama T, Simon RP et al. Bax kappa, a novel Bax splice variant from ischemic rat brain lacking an ART domain, promotes neuronal cell death. J Neurochem 2001; 77:1508–1519.
Deckwerth TL, Elliott JL, Knudson CM, Johnson EM, Jr., Snider WD, Korsmeyer SJ. BAX is required for neuronal death after trophic factor deprivation and during development. Neuron 1996; 17:401–411.
Whitfield J, Neame SJ, Paquet L, Bernard O, Ham J. Dominant-negative c-Jun promotes neuronal survival by reducing BIM expression and inhibiting mitochondria] cytochrome c release. Neuron 2001; 29:629–643.
Putcha GV, Moulder KL, Golden JP, Bouillet P, Adams JA, Strasser A et al. Induction of BIM, a proapoptotic BH3-only BCL-2 family member, is critical for neuronal apoptosis. Neuron 2001; 29:615–628.
Harris CA, Johnson EM, Jr. Bh3-only bel-2 family members are coordinately regulated by the INK pathway and require Bax to induce apoptosis in neurons. J Biol Chem 2001; 276:37754–37760.
Leonard JR, D Sa C, Calm BR, Korsmeyer SJ, Roth KA. Bid regulation of neuronal apoptosis. Brain Res Dev Brain Res 2001; 128:187–190.
Henshall DC, Bonislawski DP, Skradski SL, Lan JQ, Meller R, Simon RP. Cleavage of bid may amplify caspase-8-induced neuronal death following focally evoked limbic seizures. Neurobiol Dis 2001; 8:568–580.
Sun YF, Yu LY, Saarma M, Timmusk T, Arumae U. Neuron-specific Bel-2 homology 3 domain-only splice variant of Bak is anti-apoptotic in neurons, but pro-apoptotic in non-neuronal cells. J Biol Chem 2001; 276:16240–16247.
Vila M, Jackson-Lewis V, Vukosavic S, Djaldetti R, Liberatore G, Offen D et al. Bax ablation prevents dopaminergic neurodegeneration in the 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine mouse model of Parkinson s disease. Proc Natl Acad Sci USA 2001; 98:2837–2842.
Offen D, Beart PM, Cheung NS, Pascoe CJ, Hochman A, Gorodin S et al. Transgenic mice expressing human Bel-2 in their neurons are resistant to 6-hydroxydopamine and 1-methyl4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity. Proc Natl Acad Sci USA 1998; 95:5789–5794.
Feinstein E, Kimchi A, Wallach D, Boldin M, Varfolomeev E. The death domain: A module shared by proteins with diverse cellular functions. Trends Biochem Sci 1995; 20:342–344.
Vukosavic S, Stefanis L, Jackson-Lewis V, Guegan C, Romero N, Chen C et al. Delaying caspase activation by Bel-2: A clue to disease retardation in a transgenic mouse model of amyotrophic lateral sclerosis. J Neurosci 2000; 20:9119–9125.
Martin LJ. Neuronal death in amyotrophic lateral sclerosis is apoptosis: Possible contribution of a programmed cell death mechanism. J Neuropathol Exp Neurol 1999; 58:459–471.
Gonzalez de Aguilar JL, Gordon JW, Rene F, de Tapia M, Lutz-Bucher B, Gaiddon C et al. Alteration of the Bel-x/Bax ratio in a transgenic mouse model of amyotrophie lateral sclerosis: Evidence for the implication of the p53 signaling pathway. Neurobiol Dis 2000; 7:406–415.
Guegan C, Vila M, Rosoklija G, Hays AP, Przedborski S. Recruitment of the mitochondrialdependent apoptotic pathway in amyotrophic lateral sclerosis. J Neurosci 2001; 21:6569–6576.
Azzouz M, Hottinger A, Paterna JC, Zum AD, Aebischer P, Bueler H. Increased motoneuron survival and improved neuromuscular function in transgenic ALS mice after intraspinal injection of an adeno-associated virus encoding Bel-2. Hum Mol Genet 2000; 9:803–811.
Kostic V, Jackson-Lewis V, de Bilbao F, Dubois-Dauphin M, Przedborski S. Bel-2: Prolonging life in a transgenic mouse model of familial amyotrophic lateral sclerosis. Science 1997; 277:559–562.
Iwahashi H, Eguchi Y, Yasuhara N, Hanafusa T, Matsuzawa Y, Tsujimoto Y. Synergistic anti-apoptotic activity between Bel-2 and SMN implicated in spinal muscular atrophy. Nature 1997; 390:413–417.
Convert DD, Le TT, Morris GE, Man NT, Kralewski M, Sendtner M et al. Does the survival motor neuron protein (SMN) interact with Bel-2? J Med Genet 2000; 37:536–539.
Bernardi P, Scorrano L, Colonna R, Petronilli V, Di Lisa F. Mitochondria and cell death. Mechanistic aspects and methodological issues. Eur J Biochem 1999; 264:687–701.
Zamzami N, Kroemer G. The mitochondrion in apoptosis: How Pandora s box opens. Nat Rev Mol Cell Biol 2001; 2:67–71.
Budd SL, Tenneti L, Lishnak T, Lipton SA. Mitochondrial and extramitochondrial apoptotic signaling pathways in cerebrocortical neurons. Proc Natl Acad Sei USA 2000; 97:6161–6166.
Susin SA, Lorenzo HK, Zamzami N, Marzo I, Snow BE, Brothers GM et al. Molecular characterization of mitochondrial apoptosis-inducing factor. Nature 1999; 397:441–446.
Li LY, Luo X, Wang X. Endonuclease G is an apoptotic DNase when released from mitochondria. Nature 2001; 412:95–99.
Troy CM, Rabacchi SA, Hohl JB, Angelastro JM, Greene LA, Shelanski ML. Death in the balance: alternative participation of the caspase-2 and -9 pathways in neuronal death induced by nerve growth factor deprivation. J Neurosci 2001; 21:5007–5016.
Parrish J, Li L, Klotz K, Ledwich D, Wang X, Xue D. Mitochondrial endonuclease G is important for apoptosis inC. elegans.Nature 2001; 412:90–94
Yuan J, Shaham S, Ledoux S, Ellis HM, Horvitz HR. TheC. eleganscell death gene ced-3 encodes a protein similar to mammalian interleukin-1 beta-converting enzyme. Cell 1993; 75:641–652.
Alnemri ES, Livingston DJ, Nicholson DW, Salvesen G, Thornberry NA, Wong WW et al. Human ICE/CED-3 protease nomenclature. Cell 1996; 87:171.
Stennicke HR, Salvesen GS. Caspases Controlling intracellular signals by protease zymogen activation. Biochim Biophys Acta 2000; 1477:299–306.
Eckhart L, Declercq W, Ban J, Rendl M, Lengauer B, Mayer C et al. Terminal differentiation of human keratinocytes and stratum corneum formation is associated with caspase-14 activation. J Invest Dermatol 2000; 115:1148–1151.
Kuechle MK, Predd HM, Fleckman P, Dale BA, Presland RB. Caspase-14, a keratinocyte specific caspase: mRNA splice variants and expression pattern in embryonic and adult mouse. Cell Death Differ 2001; 8:868–870.
Sanchez Mejia RO, Ona VO, Li M, Friedlander RM. Minocycline reduces traumatic brain injury-mediated caspase-1 activation, tissue damage, and neurological dysfunction. Neurosurgery 2001; 48:1393–1399; discussion 1399–1401.
Shibata M, Hisahara S, Hara H, Yamawaki T, Fukuuchi Y, Yuan J et al. Caspases determine the vulnerability of oligodendrocytes in the ischemic brain. J Clin Invest 2000; 106:643–653.
Hisahara S, Yuan J, Momoi T, Okano H, Miura M. Caspase-11 mediates oligodendrocyte cell death and pathogenesis of autoimmune-mediated demyelination. J Exp Med 2001; 193:111–122.
Grimm S, Stanger BZ, Leder P. RIP and FADD: two death domain -containing proteins can induce apoptosis by convergent, but dissociable, pathways. Proc Natl Acad Sci USA 1996; 93:10923–10927.
Zou H, Li Y, Liu X, Wang X. An APAF-l.cytochrome c multimeric complex is a functional apoptosome that activates procaspase-9. J Biol Chem 1999; 274:11549–11556.
Srinivasula SM, Ahmad M, Fernandes-Alnemri T, Alnemri ES. Autoactivation of procaspase9 by Apaf-l-mediated oligomerization. Mol Cell 1998; 1:949–957.
Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES et al. Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 1997; 91:479–489.
Hu Y, Benedict MA, Ding L, Nunez G. Role of cytochrome c and dATP/ATP hydrolysis in Apaf-l-mediated caspase-9 activation and apoptosis. Embo J 1999; 18:3586–3595.
Chu ZL, Pio F, Xie Z, Welsh K, Krajewska M, Krajewski S et al. A novel enhancer of the Apafl apoptosome involved in cytochrome c-dependent caspase activation and apoptosis. J Biol Chem 2001; 276:9239–9245.
Fujita E, Jinbo A, Matuzaki H, Konishi H, Kikkawa U, Momoi T. Akt phosphorylation site found in human caspase-9 is absent in mouse caspase-9. Biochem Biophys Res Commun 1999; 264:550–555.
Namura S, Zhu J, Fink K, Endres M, Srinivasan A, Tomaselli KJ et al. Activation and cleavage of caspase-3 in apoptosis induced by experimental cerebral ischemia. J Neurosci 1998; 18:3659–3668.
Hartmann A, Hunot S, Michel PP, Muriel MP, Vyas S, Faucheux BAetal. Caspase-3: A vulnerability factor and final effector in apoptotic death of dopaminergic neurons in Parkinson s disease. Proc Natl Acad Sci USA 2000; 97:2875–2880.
Su JH, Zhao M, Anderson AJ, Srinivasan A, Cotman CW. Activated caspase-3 expression in Alzheimer s and aged control brain: Correlation with Alzheimer pathology. Brain Res 2001; 898:350–357.
Li M, Ona VO, Chen M, Kaul M, Tenneti L, Zhang X et al. Functional role and therapeutic implications of neuronal caspase-1 and -3 in a mouse model of traumatic spinal cord injury. Neuroscience 2000; 99:333–342.
Tenneti L, Lipton SA. Involvement of activated caspase-3-like proteases in N-methyl-Daspartate-induced apoptosis in cerebrocortical neurons. J Neurochem 2000; 74:134–142.
Benchoua A, Guegan C, Couriaud C, Hosseini H, Sampaio N, Morin D et al. Specific caspase pathways are activated in the two stages of cerebral infarction. J Neurosci 2001; 21:7127–7134.
Chen M, Ona VO, Li M, Ferrante RJ, Fink KB, Zhu S et al. Minocycline inhibits caspase1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease. Nat Med 2000; 6:797–801.
Kuida K, Zheng TS, Na S, Kuan C, Yang D, Karasuyama H et al. Decreased apoptosis in the brain and premature lethality in CPP32- deficient mice. Nature 2000; 384:368–372.
LeBlanc A, Liu H, Goodyer C, Bergeron C, Hammond J. Caspase-6 role in apoptosis of human neurons, amyloidogenesis, and Alzheimer s disease. J Biol Chem 1999; 274:23426–23436.
Wellington CL, Singaraja R, Ellerby L, Savill J, Roy S, Leavitt B et al. Inhibiting caspase cleavage of huntingtin reduces toxicity and aggregate formation in neuronal and nonneuronal cells. J Biol Chem 2000; 275:19831–19838.
Selznick LA, Zheng TS, Flavell RA, Rakic P, Roth KA. Amyloid beta-induced neuronal death is Bax-dependent but caspase-independent. J Neuropathol Exp Neurol 2000; 59:271–279.
D Mello SR, Kuan CY, Flavell RA, Rakic P. Caspase-3 is required for apoptosis-associated DNA fragmentation but not for cell death in neurons deprived of potassium. J Neurosci Res 2000; 59:24–31.
Droin N, Beauchemin M, Solary E, Bertrand R. Identification of a caspase-2 isoform that behaves as an endogenous inhibitor of the caspase cascade. Cancer Res 2000; 60:7039–7047.
Tschopp J, Irmler M, Thome M. Inhibition of fas death signals by FLIPs. Curr Opin Immunol 1998; 10:552–558.
Cheema ZF, Wade SB, Sata M, Walsh K, Sohrabji F, Miranda RC. Fas/Apo [apoptosis]-1 and associated proteins in the differentiating cerebral cortex: induction of caspase-dependent cell death and activation of NF-kappaB. J Neurosci 1999; 19:1754–1770.
Yeh WC, Itie A, Elia AJ, Ng M, Shu HB, Wakeham A et al. Requirement for Casper (c-FLIP) in regulation of death receptor-induced apoptosis and embryonic development. Immunity 2000; 12:633–642.
Yang YL, Li XM. The IAP family: Endogenous caspase inhibitors with multiple biological activities. Cell Res 2000; 10:169–177.
Holcik M, Korneluk RG. XIAP, the guardian angel. Nat Rev Mol Cell Biol 2001; 2:550–556.
Yang Y, Fang S, Jensen JP, Weissman AM, Ashwell JD. Ubiquitin protein ligase activity of IAPs and their degradation in proteasomes in response to apoptotic stimuli. Science 2000; 288:874–877.
Liston P, Fong WG, Kelly NL, Toji S, Miyazaki T, Conte D et al. Identification of XAF1 as an antagonist of XIAP anti-Caspase activity. Nat Cell Biol 2001; 3:128–133.
Verhagen AM, Ekert PG, Pakusch M, Silke J, Connolly LM, Reid GE et al. Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins. Cell 2000; 102:43–53.
Du C, Fang M, Li Y, Li L, Wang X. Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. Cell 2000; 102:33–42.
Siman R, Noszek JC. Excitatory amino acids activate calpain I and induce structural protein breakdown in vivo. Neuron 1988; 1:279–287.
Siman R, Noszek JC, Kegerise C. Calpain I activation is specifically related to excitatory amino acid induction of hippocampal damage. J Neurosci 1989; 9:1579–1590.
Saatman KE, Bozyczko-Coyne D, Marcy V, Siman R, McIntosh TK. Prolonged calpainmediated spectrin breakdown occurs regionally following experimental brain injury in the rat. J Neuropathol Exp Neurol 1996; 55:850–860.
Saatman KE, Murai H, Bartus RT, Smith DH, Hayward NJ, Perri BR et al. Calpain inhibitor AK295 attenuates motor and cognitive deficits following experimental brain injury in the rat. Proc Natl Acad Sci USA 1996; 93:3428–3433.
Faddis BT, Hasbani MJ, Goldberg MP. Calpain activation contributes to dendritic remodeling after brief excitotoxic injury in vitro. J Neurosci 1997; 17:951–959.
Kampfl A, Posmantur RM, Zhao X, Schmutzhard E, Clifton GL, Hayes RL. Mechanisms of calpain proteolysis following traumatic brain injury: Implications for pathology and therapy: Implications for pathology and therapy: a review and update. J Neurotrauma 1997; 14:121–134.
Rami A, Ferger D, Krieglstein J. Blockade of calpain proteolytic activity rescues neurons from glutamate excitotoxicity. Neurosci Res 1997; 27:93–97.
Scarisbrick IA, Towner MD, Isackson PJ. Nervous system-specific expression of a novel serine protease: Regulation in the adult rat spinal cord by excitotoxic injury. J Neurosci 1997; 17:8156–816
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2003 Springer Science+Business Media New York
About this chapter
Cite this chapter
Morrison, R.S., Kinoshita, Y., Johnson, M.D., Ghatan, S., Ho, J.T., Garden, G. (2003). Neuronal Survival and Cell Death Signaling Pathways. In: Alzheimer, C. (eds) Molecular and Cellular Biology of Neuroprotection in the CNS. Advances in Experimental Medicine and Biology, vol 513. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-0123-7_2
Download citation
DOI: https://doi.org/10.1007/978-1-4615-0123-7_2
Publisher Name: Springer, Boston, MA
Print ISBN: 978-1-4613-4934-1
Online ISBN: 978-1-4615-0123-7
eBook Packages: Springer Book Archive