磷脂酶 A2 (phospholipase A2; PLA2) 為一在鈣離子存在下會水解1,2-diacyl-3-sn-phosphoglycerides 之 2-acyl ester bond 的酵素，且釋放出之產物 fatty acids 及 lysophospholipids 為調控許多生理功能如脂質代謝、細胞分泌及發炎反應等訊息分子之前驅物。 因此 PLA2 不僅在維持正常生理功能上扮演重要的角色，也參與許多發炎相關疾病。 然而其導致細胞死亡的機制仍未釐清。 本研究主旨主要為利用 Naja naja atra PLA2 來處理人類神經母細胞瘤細胞 SK-N-SH 及血癌細胞 K562，並探討 PLA2 誘導細胞死亡的訊息傳遞路徑。 經 PLA2 處理 SK-N-SH 及 K562 細胞後，可觀察到 p38 mitogen-activated protein kinase (p38 MAPK) 或 c-Jun N-terminal kinase (JNK) 活化、extracellularsignal-regulated protein kinase (ERK) 去磷酸化、reactive oxygen species (ROS) 產生、[Ca2+]i 濃度增加、粒線體膜電位喪失 (ΔΨm)、 cytochrome c釋放及 Fas/FasL 蛋白質表現等現象。 分別處理 N-Acetylcysteine (ROS 清除劑)、BAPTA-AM (Ca2+ 螯和劑)、SB202190 (p38 MAPK 抑制劑) 或 SP600125 (JNK 抑制劑) 則可抑制 p38 MAPK 或 JNK 活化並回復細胞生存率、ΔΨm 喪失、 cytochrome c 釋放及抑制 Fas/FasL 蛋白質表現等現象，也促使 ERK 回復磷酸化。 ERK 的活化可減緩 p38 MAPK 所調節 Fas/FasL 表現的效應。 此外，SB202190 及 PLA2共同處理K562 細胞後，可觀察到 p38 MAPK 活性的下降進而造成 JNK 持續活化來促使細胞死亡。 而利用 siRNA 等技術則發現在 K562 細胞中 PLA2 藉由活化 p38 MAPK/ATF-2 或 JNK1/c-Jun 等路徑來調控 Fas/FasL 基因表現。 此外，無酵素活性之 PLA2 處理細胞後仍可造成 Fas/FasL 蛋白質表現及細胞死亡。
利用 PLA2 的水解產物 arachidonic acid (AA) 及 lysophosphatidylcholine (LPC) 處理上述兩種細胞後並不引發 Fas/FasL 蛋白質表現。 並由結果得知 AA 誘導 ROS 及 [Ca2+]i 濃度上升來活化 p38 MAPK/JNK，並藉此破壞粒線體正常運作而導致細胞死亡。 此外，額外使用 U0126 來抑制 ERK 活化則有增進 AA 調控 Fas/FasL 蛋白質表現的能力。 綜合上述結果確認 PLA2 可藉由 [Ca2+]i 及 ROS 來活化 p38 MAPK 或 JNK 並誘導 Fas/FasL 蛋白質表現來部份參與細胞死亡機制。

The enzyme phospholipase A2 (PLA2) specifically hydrolyzes the 2-acyl ester bond of 1,2-diacyl-3-sn-phosphoglycerides releasing fatty acids and lysophospholipids in the presence of Ca2+. Both products represent precursors for signaling molecules that can exert a multitude of biological functions including phospholipid metabolism, exocytosis and inflammation. Consequently, PLA2 not only plays a role in regulating physiological processes, but also exhibits pharmacological effects in inflammatory diseases. Nevertheless, the signaling pathway leading to cell death still remains elusive. In the present study, the cytotoxicity of Naja naja atra PLA2 toward human neuroblastoma SK-N-SH cells and leukemia K562 cells were respectively evaluated to explore the signaling pathway of PLA2-induced cell death. Upon exposure to PLA2, p38 mitogen-activated protein kinase (p38 MAPK) or c-Jun N-terminal kinase (JNK) activation, extracellularsignal-regulated protein kinase (ERK) inactivation, reactive oxygen species (ROS) generation, increase in intracellular Ca2+ concentration, the loss of mitochondrial membrane potential (ΔΨm), cytochrome c release and upregulation of Fas/FasL were found in SK-N-SH or K562 cells. N-Acetylcysteine (ROS scavenger), BAPTA-AM (Ca2+ chelator), SB202190 (p38 MAPK inhibitor) or SP600125 (JNK inhibitor) abrogated p38 MAPK or JNK activation and rescued cell viability, ΔΨm, cytochrome c release and suppressed Fas/FasL upregulation of PLA2-treated cells, but restored phosphorylation of ERK. Activated ERK was found to attenuate p38 MAPK-mediated upregulation of Fas/FasL. Besides, sustained JNK activation was also observed in SB202190/PLA2-treated K562 cells after exterminating p38 MAPK activation, but also retained the cytotoxicity of PLA2. Knockdown of p38 MAPK or JNK1 by siRNA proved that PLA2 induced Fas/FasL upregulation through p38 MAPK/ATF-2 or JNK1/c-Jun pathways in K562 cells. Furthermore, deprivation of catalytic activity could not diminish PLA2-induced cell death and Fas/FasL upregulation.
The cytotoxicity of arachidonic acid (AA) and lysophosphatidylcholine (LPC) was not related to the expression of Fas/FasL. The results showed that the cytotoxicity of AA is mediated through mitochondria-dependent death pathway, eliciting by AA-induced ROS generation and Ca2+-evoked activation of p38 MAPK and JNK. Besides, ERK activation abrogated by U0126 improved the ability of AA-mediated Fas/FasL upregulation in K562 cells. Taken together, our results indicate that PLA2-induced cell death is through Ca2+- and ROS evoked p38 MAPK or JNK activation. Upregulation of Fas/FasL partially involves in cytotoxicity of PLA2.

中文摘要 …………………………………………………… 5
英文摘要 …………………………………………………… 7
緒論 …………………………………………………… 9
圖1∼圖4 …………………………………………………… 19
縮寫表 …………………………………………………… 23
實驗材料 …………………………………………………… 24
實驗方法 …………………………………………………… 26
I. PLA2 對 SK-N-SH 細胞的毒殺機制 …………………… 35
實驗目的 …………………………………………………… 36
結果 …………………………………………………… 38
圖5∼圖19 …………………………………………………… 44
II. AA 對 SK-N-SH 細胞的毒殺機制 ……………………… 59
實驗目的 …………………………………………………… 60
結果 …………………………………………………… 62
圖20∼圖33 …………………………………………………… 68
III. PLA2 對 K562 細胞的毒殺機制 ……………………… 82
實驗目的 …………………………………………………… 83
結果 …………………………………………………… 85
圖34∼圖52 …………………………………………………… 94
IV. AA 對 K562 細胞的毒殺機制 ………………………… 113
實驗目的 …………………………………………………… 114
結果 …………………………………………………… 116
圖53∼圖68 ………………………………………………… 121
討論 …………………………………………………… 137
參考文獻 …………………………………………………… 143
歷年發表作品 ……………………………………………… 172

Abe, A. and Shayman, J. A. (1998) Purification and characterization of 1-Oacylceramide synthase, a novel phospholipase A2 with transacylase activity. J. Biol. Chem. 273, 8467-8474.

Abe, A., Hiraoka, M., Wild, S., Wilcoxen, S. E., Paine 3rd, R. and Shayman, J. A. (2004) Lysosomal phospholipase A2 is selectively expressed in alveolar macrophages. J. Biol. Chem. 279, 42605-42611.

Ackermann, E. J., Kempner, E. S. and Dennis, E. A. (1994) Ca2+- independent cytosolic phospholipase A2 from macrophage-like P388D1 cells. Isolation and characterization. J. Biol. Chem. 269, 9227-9233.

Adibhatla, R. M., Hatcher, J. F. and Dempsey, R. J. (2003) Phospholipase A2, hydroxyl radicals, and lipid peroxidation in transient cerebral ischemia. Antioxid. Redox Signal. 5, 647-654.

Adibhatla, R. M., Hatcher, J. F. and Dempsey, R. J. (2006) Lipids and lipidomics in brain injury and diseases. AAPS J. 8, 314-321.

Adler, D. H., Cogan, J. D., Phillips 3rd, J. A., Schnetz-Boutaud, N., Milne, G. L., Iverson, T., Stein, J. A., Brenner, D. A., Morrow, J. D., Boutaud, O. and Oates, J. A. (2008) Inherited human cPLA2 deficiency is associated with impaired eicosanoid biosynthesis, small intestinal ulceration, and platelet dysfunction. J. Clin. Invest. 118, 2121-2131.

Almeida, T., Cunha, R. A. and Ribeiro, J. A. (1999) Facilitation by arachidonic acid of acetylcholine release from the rat hippocampus. Brain Res. 826, 104-111.

Anthonsen, M. W., Solhaug, A. and Johansen, B. (2001) Functional coupling between secretory and cytosolic PLA2 modulates TNF-a- and IL-1a-induced NF-kB activation. J. Biol. Chem. 276, 30527-30536.

Ashkenazi, A. (2002) Targeting death and decoy receptors of the tumour-necrosis factor superfamily. Nat. Rev. Cancer, 2, 420-430.

Balboa, M. A., Balsinde, J., Winstead, M. V., Tischfield, J. A. and Dennis, E. A. (1996) Novel group V phospholipase A2 involved in arachidonic acid mobilization in murine P388D1 macrophages. J. Biol. Chem. 271, 32381-32384.

Balboa, M. A., Balsinde, J., Jones, S. S. and Dennis, E. A. (1997) Identity between the Ca2+-independent phospholipase A2 enzymes from P388D1 macrophages and Chinese hamster ovary cells. J. Biol. Chem. 272, 8576-8580.

Balsinde, J. and Balboa, M. A. (2005) Cellular regulation and proposed biological functions of group VIA calcium-independent phospholipase A2 in activated cells. Cell Signal. 17, 1052-1062.

Banfi, B., Molnar, G., Maturana, A., Steger, K., Hegedus, B., Demaurex, N. and Krause, K. H. (2001) A Ca2+-activated NADPH oxidase in testis, spleen and lymph nodes. J. Biol. Chem. 276, 37594-37601.

Bao, S., Miller, D. J., Ma, Z., Wohltmann, M., Eng, G., Ramanadham, S., Moley, K. and Turk, J. (2004) Male mice that do not express group VIA phospholipase A2 produce spermatozoa with impaired motility and have greatly reduced fertility. J. Biol. Chem. 279, 38194-38200.

Bao, S., Song, H., Wohltmann, M., Ramanadham, S., Jin, W., Bohrer, A. and Turk, J. (2006) Insulin secretory responses and phospholipid composition of pancreatic islets from mice that do not express Group VIA phospholipase A2 and effects of metabolic stress on glucose homeostasis. J. Biol. Chem. 281, 20958-20973.

Bao, S., Li, Y., Lei, X., Wohltmann, M., Jin, W., Bohrer, A., Semenkovich, C. F., Ramanadham, S., Tabas, I. and Turk, J. (2007) Attenuated free cholesterol loading-induced apoptosis but preserved phospholipid composition of peritoneal macrophages from mice that do not express group VIA phospholipase A2. J. Biol. Chem. 282, 27100-27114.

Baranda-Avila, N., Mendoza-Rodríguez, C. A., Morimoto, S., Langley, E. and Cerbón, M. (2009) Molecular mechanism of cell proliferation in rodent uterus during the estrous cycle. J. Steroid Biochem. Mol. Biol. 113, 259-268.

Baskakis, C., Magrioti, V., Cotton, N., Stephens, D., Constantinou-Kokotou, V., Dennis, E. A. and Kokotos, G. (2008) Synthesis of poly-fluoroketones for selective inhibition of human phospholipase A2 enzymes. J. Med. Chem. 51, 8027-8037.

Basu, A. and Haldar, S. (2003) Identification of a novel Bcl-xL phosphorylation site regulating the sensitivity of taxol- or 2-methoxyestradiol-induced apoptosis. FEBS Lett. 538, 41-47.

Bechmann, I., Mor, G., Nilsen, J., Eliza, M., Nitsch, R. and Naftolin, F. (1999) FasL (CD95L, Apo1L) is expressed in the normal rat and human brain: evidence for the existence of an immunological brain barrier. Glia. 27, 62-74.

Bechmann, I., Lossau, S., Steiner, B., Mor, G., Gimsa, U. and Nitsch, R. (2000) Reactive astrocytes upregulate Fas (CD95) and Fas ligand (CD95L) expression but do not undergo programmed cell death during the course of anterograde degeneration. Glia. 32, 25-41.

Bedi, A., Barber, J. P., Bedi, G. C., El-Deiry, W. S., Sidransky, D., Vala, M. S., Akhtar, A. J., Hilton, J. and Jones, R. J. (1995) BCR-ABL-mediated inhibition of apoptosis with delay of G2/M transition after DNA damage: A mechanism of resistance to multiple anticancer agents. Blood 86, 1148-1158.

Beer, R., Franz, G., Schopf, M., Reindl, M., Zelger, B., Schmutzhard, E., Poewe, W. and Kampfl, A. (2000) Expression of Fas and Fas ligand after experimental traumatic brain injury in the rat. J. Cereb. Blood Flow Metab. 2, 669-677.

Bickler, P. E. and Fahlman, C. S. (2006) The inhaled anesthetic, isoflurane, enhances Ca2+-dependent survival signaling in cortical neurons and modulates MAP kinases, apoptosis proteins and transcription factors during hypoxia. Anesth. Analg. 103, 419-429.

Biedler, J. L., Roffler-Tarlov, S., Schachner, M. and Freedman, L. S. (1978) Multiple neurotransmitter synthesis by human neuroblastoma cell lines and clones. Cancer Res. 33, 2643-2652.

Boilard, E., Rouault, M., Surrel, F., Le Calvez, C., Bezzine, S., Singer, A., Gelb, M. H. and Lambeau, G. (2006) Secreted phospholipase A2 inhibitors are also potent blockers of binding to the M-type receptor. Biochemistry 45, 13203-13218.

Bonetti, B., Pohl, J., Gao, Y. L. and Raine, C. S., (1997) Cell death during autoimmune demyelination: effector but not target cells are eliminated by apoptosis. J. Immunol. 159, 5733-5741.

Bonventre, J. V., Huang, Z., Taheri, M. R., O’Leary, E., Li, E., Moskowitz, M. A. and Sapirstein, A. (1997) Reduced fertility and postischaemic brain injury in mice deficient in cytosolic phospholipase A2. Nature 390, 622-625.

Borutaite, V., Hope, H. and Brown, G. C. (2006) Arachidonate and NADPH oxidase synergise with iNOS to induce death in macrophages: mechanisms of inflammatory degeneration. Pharmacol. Rep. 58 Suppl, 96-102.

Boyanovsky, B. and Webb, N. (2009) Biology of secretory phospholipase A2. Cardiovasc. Drugs Ther. 23, 61-72.

Boylan, M. T., Crockard, A. D., McDonnell, G. V., McMillan, S. A. and Hawkins, S. A. (2001) Serum and cerebrospinal fluid soluble Fas levels in clinical subgroups of multiple sclerosis. Immunol. Lett. 78, 183-187.

Breitschopf, K., Haendeler, J., Malchow, P., Zeiher, A. M. and 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.

Brozovic, A., Fritz, G., Christmann, M., Zisowsky, J., Jaehde, U., Osmak, M. and Kaina, B. (2004) Long-term activation of SAPK/JNK, p38 kinase and fas-L expression by cisplatin is attenuated in human carcinoma cells that acquired drug resistance. Int. J. Cancer 112, 974-985.

Bruder, J. M., Spaulding, A. J. and Wierman, M. E. (1996) Phorbol ester inhibition of rat gonadotropin-releasing hormone promoter activity: role of Fos and Jun in the repression of transcription. Mol. Endocrinol. 10, 35-44.

Buckland, A. G., Heeley, E. L. and Wilton, D. C. (2000) Bacterial cell membrane hydrolysis by secreted phospholipases A2: a major physiological role of human group IIa sPLA2 involving both bacterial cell wall penetration and interfacial catalysis. Biochim. Biophys. Acta. 1484, 195-206.

Buckland, A. G. and Wilton, D. C. (2000) The antibacterial properties of secreted phospholipases A2. Biochim. Biophys. Acta. 1488, 71-82.

Burke, J. E., Hsu, Y. H., Deems, R. A., Li, S., Woods, Jr., V. L. and Dennis, E. A. (2008) A phospholipid substrate molecule residing in the membrane surface mediates opening of the lid region in group IVA cytosolic phospholipase A2. J. Biol. Chem. 283, 31227-31236.

Burke, J. E., Karbarz, M. J., Deems, R. A., Li, S., Woods, Jr., V. L. and Dennis, E. A. (2008) Interaction of group IA phospholipase A2 with metal ions and phospholipid vesicles probed with deuterium exchange mass spectrometry. Biochemistry 47, 6451-6459.
Burke, J. E. and Dennis, E. A. (2009a) Phospholipase A2 biochemistry. Cardiovasc. Drugs Ther. 23, 49-59.

Burke, J. E. and Dennis, E. A. (2009b) Phospholipase A2 structure/function, mechanism, and signaling. J. Lipid Res. 50 Suppl, 237-242.

Calvete, J. J., Juárez, P. and Sanz, L. (2007) Snake venomics. Strategy and applications. J. Mass Spectrom. 42, 1405-1414.

Camins, A., Pallas, M. and Silvestre, J. S. (2008) Apoptotic mechanisms involved in neurodegenerative diseases: Experimental and therapeutic approaches. Methods Find Exp. Clin. Pharmacol. 30, 43-65.

Cao, Y., Pearman, A. T., Zimmerman, G. A., McIntyre, T. M. and Prescott , S. M. (2000) Intracellular unesterified arachidonic acid signals apoptosis. Proc. Natl. Acad. Sci. 10, 11280-11285.

Carman, G. M., Deems, R. A. and Dennis, E. A. (1995) Lipid signaling enzymes and surface dilution kinetics. J. Biol. Chem. 270, 18711-18714.

Casha, S., Yu, W. R. and Fehlings, M. G. (2001) Oligodendroglial apoptosis occurs along degenerating axons and is associated with FAS and p75 expression following spinal cord injury in the rat. Neuroscience 103, 203-218.

Chang, L., Kamata, H., Solinas, G., Luo, J. L., Maeda, S., Venuprasad, K., Liu, Y. C. and Karin, M. (2006) The E3 ubiquitin ligase itch couples JNK activation to TNFalpha-induced cell death by inducing c-FLIP(L) turnover. Cell 124, 601-613.

Chang, L. S., Kuo, K. W. and Chang, C. C. (1993) Identification of functional involvement of tryptophan residues in phospholipase A2 from Naja naja atra (Taiwan cobra) snake venom. Biochim. Biophys. Acta. 1202, 216-220.

Chang, L. S., Hung, J. J., Lin, S., Chang, C. C. (1994) Chemical modification of Lys-6 in Taiwan cobra phospholipase A2 with 4-chloro-3,5-dinitrobenzoate. Biochem. Mol. Biol. Int. 33, 1207-1213.

Chang, L. S., Lin, S. R. and Chang, C. C. (1996) The essentiality of calcium ion in the enzymatic activity of Taiwan cobra phospholipase A2. J. Protein Chem. 15, 701-707.

Chang, L. S., Lin, S. R. and Chang, C. C. (1997) Probing calcium ion-induced conformational changes of Taiwan cobra phospholipase A2 by trinitrophenylation of lysine residues. J. Protein Chem. 16, 51-57.

Chang, L. S., Lin, S. R. and Chang, C. C. (1998) Identification of Arg-30 as the essential residue for the enzymatic activity of Taiwan cobra phospholipase A2. J. Biochem. (Tokyo) 124, 764-768.

Chang, L. S., Cheng, Y. C. and Chen, C. P. (2006) Modification of Lys-6 and Lys-65 affects the structural stability of Taiwan cobra phospholipase A2. Protein J. 25, 127-134.

Chen, J. K., Capdevila, J. and Harris, R. C. (2001) Cytochrome p450 epoxygenase metabolism of arachidonic acid inhibits apoptosis. Mol. Cell Biol. 21, 6322-6331.

Chen, J., S. Engle, J., Seilhamer, J. J. and Tischfield, J. A. (1994) Cloning and recombinant expression of a novel human low-molecularweight Ca2+-dependent phospholipase A2. J. Biol. Chem. 269, 2365-2368.

Chiba, H., Michibata, H., Wakimoto, K., Seishima, M., Kawasaki, S., Okubo, K., Mitsui, H., Torii, H. and Imai, Y. (2004) Cloning of a gene for a novel epithelium-specific cytosolic phospholipase A2, cPLA2, induced in psoriatic skin. J. Biol. Chem. 279, 12890-12897.

Chiou, Y. L., Cheng, Y. C., Kao, P. H., Wang, J. J. and Chang, L. S. (2008) Mutations on the N-terminal region abolish differentially the enzymatic activity, membrane-damaging activity and cytotoxicity of Taiwan cobra phospholipase A2. Toxicon 51, 270-279.

Choi, C. and Benveniste, E. N. (2004) Fas ligand/Fas system in the brain: regulator of immune and apoptotic responses. Brain Res. Brain Res. Rev. 44, 65-81.

Chow, S. C., Sisfontes, L., Bjorkhem, I. and Jondal, M. (1989) Suppression of growth in a leukemic T cell line by n-3 and n-6 polyunsaturated fatty acids. Lipids 24, 700-704.

Christmann, M., Tomicic, M. T., Aasland, D. and Kaina, B. (2007) A role for UV-light-induced c-Fos: Stimulation of nucleotide excision repair and protection against sustained JNK activation and apoptosis. Carcinogenesis 28, 183-190.

Clark, J. D., Lin, L. L., Kriz, R. W., Ramesha, C. S., Sultzman, L. A., Lin, A. Y., Milona, N. and Knopf, J. L. (1991) A novel arachidonic acid-selective cytosolic PLA2 contains a Ca2+-dependent translocation domain with homology to PKC and GAP. Cell 65, 1043-1051.

Comes, F., Matrone, A., Lastella, P., Nico, B., Susca, F. C., Bagnulo, R., Ingravallo, G., Modica, S., Lo Sasso, G., Moschetta, A., Guanti, G., Simone, C. (2007) A novel cell type-specific role of p38alpha in the control of autophagy and cell death in colorectal cancer cells. Cell Death Differ. 14, 693-702.

Condrea, E., Fletcher, J. E., Rapuano, B. E., Yang, C. C. and Rosenberg, P. (1981) Dissociation of enzymatic activity from lethality and pharmacological properties by carbamylation of lysines in Naja nigricollis and Naja naja atra snake venom phospholipases A2. Toxicon 19, 705-720.

Crist, S. A., Griffith, T. S. and Ratliff, T. L. (2003) Structure/function analysis of the murine CD95L promoter reveals the identification of a novel transcriptional repressor and functional CD28 response element. J. Biol. Chem. 278, 35950-35958.

Daniel, P. T., Scholz, C., Westermann, J., Dorken, B., Pezzutto, A. (1998) Dendritic cells prevent CD95-mediated T lymphocyte death through costimulatory signals. Gene Ther. Cancer 28, 173-177.

Davis, R. J. (2000) Signal transduction by the JNK group of MAP kinases. Cell 103, 239-252.

De Chiara, G., Marcocci, M. E., Torcia, M., Lucibello, M., Rosini, P., Bonini, P., Higadshimoto,Y., Damonte, G., Armirotti, A., Amodei, S., Palamara, A. T., Russo, T., Garsci, E. and Cozzolino, F. (2006) Bcl-2 phosphorylation by p38 MAPK, Identification of target sites and biologic consequences. J. Biol. Chem. 281, 21353-21361.

DeCoster, M. A., Lambeau, G., Lazdunski, M. and Bazan, N. G. (2002) Secreted phospholipase A2 potentiates glutamate-induced calcium increase and cell death in primary neuronal cultures. J. Neurosci. Res. 67, 634-645.

Dennis, E. A. (1994) Diversity of group types, regulation, and function of phospholipase A2. J. Biol. Chem. 269, 13057-13060.

Denson, D. D., Wang, X., Worrell, R. T. and Eaton, D. C. (2000) Effects of fatty acids on BK channels in GH3 cells. Am. J. Physiol. 279, 1211-1219.

Dessen, A., Tang, J., Schmidt, H., Stahl, M., Clark, J. D., Seehra, J. and Somers, W. S. (1999) Crystal structure of human cytosolic phospholipase A2 reveals a novel topology and catalytic mechanism. Cell 97, 349-360.

Dobreva, Z. G., Miteva, L. D. and Stanilova, S. A. (2009) The inhibition of JNK and p38 MAPKs downregulates IL-10 and differentially affects c-Jun gene expression in human monocytes. Immunopharmacol. Immunotoxicol. 23, 1-7.

Doroshenko, N. and Doroshenko, P. (2004) Ca2+ influx is not involved in acute cytotoxicity of arachidonic acid. Biochem. Pharmacol. 67, 903-909.

Dumesic, P. A., Scholl, F. A., Barragan, D. I. and Khavari, P. A. (2009) Erk1/2 MAP kinases are required for epidermal G2/M progression. J. Cell. Biol. 185, 409-422.

Eerola, L. I., Surrel, F., Nevalainen, T. J., Gelb, M. H., Lambeau, G. and Laine, V. J. (2006) Analysis of expression of secreted phospholipases A2 in mouse tissues at protein and mRNA levels. Biochim. Biophys. Acta. 1761, 745-756.

Engedal, N., Auberger, P. and Blomhoff, H. K. (2009) Retinoic acid regulates Fas-induced apoptosis in Jurkat T cells: reversal of mitogen-mediated repression of Fas DISC assembly. J. Leukoc. Biol. 85, 469-480.

Enslen, H., Raingeaud, J. and Davis, R. J. (1998) Selective activation of p38 mitogen-activated protein (MAP) kinase isoforms by the MAP kinase kinases MKK3 and MKK6. J. Biol. Chem. 273, 1741-1748.

Faris, M., Latinis, K. M., Kempiak, S. J., Koretzky, G. A. and Nel, A. (1998) Stress-induced Fas ligand expression in T cells is mediated through a MEK kinase 1-regulated response element in the Fas ligand promoter. Mol. Cell Biol. 18, 5414-5424.

Farooqui, A. A., Horrocks, L. A. and Farooqui, T. (2000) Glycerophospholipids in brain: their metabolism, incorporation into membranes, functions, and involvement in neurologic disorders. Chem. Phys. Lipids 106, 1-29.

Farooqui, A. A. and Horrocks, L. A. (2004) Brain phospholipases A2: A perspective on the history. Prostaglandins Leukot. Essent. Fatty Acids 71, 161-169.

Favre-Felix, N., Fromentin, A., Hammann, A., Solary, E., Martin, F., and Bonnette, B. (2000) Cutting edge: The tumour counterattack hypothesis revisited. Colon cancer cells do not induce T cell apoptosis via the Fas (Apo-1/CD95) pathway. J. Immunol. 164, 5023-5027.

Finstad, H. S., Kolset, S. O., Holme, J. A., Wiger, R., Farrants, A. K. Blomhoff, R. and Drevon, C. A. (1994) Effect of n-3 and n-6 fatty acids on proliferation and differentiation of promyelocytic leukemic HL-60 cells. Blood 84, 3799-3809.

Finstad, H. S., Myhrstad, M. C., Heimli H, Lømo, J., Kiil Blomhoff, H., Kolset, S. O. and Drevon, C. A. (1998) Multiplication and death-type of leukemia cell lines exposed to very long-chain polyunsaturated fatty acids. Leukemia 12, 921-929.

Flugel, A., Schwaiger, F. W., Neumann, H., Medana, I., Willem, M., Wekerle, H., Kreutzberg, G. W. and Graeber, M. B. (2000) Neuronal FasL induces cell death of encephalitogenic T lymphocytes. Brain Pathol. 10, 353-364.

Fonteh, A. N., LaPorte, T., Swan, D. and McAlexander, M. A. (2001) A decrease in remodeling accounts for the accumulation of arachidonic acid in murine mast cells undergoing apoptosis. J. Biol. Chem. 276, 1439-1449.

Fox, J. W. and Serrano, S. M. T. (2005) Snake toxins and hemostasis. Toxicon 45, 949-951.

Frigo, D. E., Tang, Y., Beckman, B. S., Scandurro, A. B., Alam, J., Burow, M. E. and McLachlan, J. A. (2004) Mechanism of AP-1-mediated gene expression by select organochlorines through the p38 MAPK pathway. Carcinogenesis 25, 249-261.

Fuentes, L., Hernandez, M., Nieto, M. L. and Crespo, M. S. (2002) Biological effects of group IIA secreted phospholipase A2. FEBS Lett. 531, 7-11.

Funk, C. D. (2001) Prostaglandins and leukotrienes: advances in eicosanoid biology. Science 294, 1871-1875.

Gabai, V. L., Meriin, A. B., Yaglom, J. A., Wei, J. Y., Mosser, D. D. and Sherman, M. Y. (2000) Suppression of stress kinase JNK is involved in HSP72-mediated protection of myogenic cells from transient energy deprivation: HSP72 alleviates the stress-induced inhibition of JNK dephosphorylation. J. Biol. Chem. 275, 38088-38094.

Gardner, A. A., Reichert, E. C., Topham, M. K., Stafforini, D. M. (2008) Identification of a domain that mediates association of plateletactivating factor acetylhydrolase with high density lipoprotein. J. Biol. Chem. 283, 17099-17106.

Gelb, M. H., Jain, M. K., Hanel, A. M. and Berg, O. G. (1995) Interfacial enzymology of glycerolipid hydrolases: lessons from secreted phospholipases A2. Annu. Rev. Biochem. 64, 653-688.

Gesbert, F., Sellers, W. R., Signoretti, S., Loda, M. and Griffin, J. D. (2000) BCR/ABL regulates expression of the cyclin-dependent kinase inhibitor p27Kip1 through the phosphatidylinositol 3-Kinase/AKT pathway. J. Biol. Chem. 275, 39223-39230.

Ghosh, M., Tucker, D. E., Burchett, S. A. and Leslie, C. C. (2006) Properties of the group IV phospholipase A2 family. Prog. Lipid Res. 45, 487-510.

Gijon, M.A. and Leslie, C. (1997) Phospholipase A2. Cell Dev. Biol. 8, 297-303.

Gilley, R., March, H. N. and Cook, S. J. (2009) ERK1/2, but not ERK5, is necessary and sufficient for phosphorylation and activation of c-Fos. Cell Signal. 21, 969-977.

Giuliano, M., Calvaruso, G., Pellerito, O., Portanova, P., Carlisi, D., Vento, R. and Tesoriere, G. (2006) Anandamide-induced apoptosis in Chang liver cells involves ceramide and JNK/AP-1 pathway. Int. J. Mol. Med. 17, 811-819.

Golstein, P. and Kroemer, G. (2006) Cell death by necrosis: towards amolecular definition. Trends Biochem. Sci. 32, 37-43.

Granata, F., Frattini, A., Loffredo, S., Del Prete, A., Sozzani, S., Marone, G. and Triggiani, M. (2006) Signaling events involved in cytokine and chemokine production induced by secretory phospholipase A2 in human lung macrophages. Eur. J. Immunol. 36, 1938-1950.

Grethe, S., Ares, M. P. S., Anderson, T. and Pore-Ares, M. I. (2004) p38 MAPK mediates TNF induce apoptosis in endothelia cells via phosphorylation and downregulation of Bcl-xL. Exp. Cell Res. 298, 632-642.

Gurney, A. L., Park, E. A., Giralt, M., Liu, J. and Hanson, R. W. (1992) Opposing actions of Fos and Jun on transcription of the phosphoenolpyruvate carboxykinase (GTP) gene. Dominant negative regulation by Fos. J. Biol.Chem. 267, 18133-18139.

Hail, Jr. N. (2005) Mitochondria: a novel target for the chemoprevention of cancer. Apoptosis 10, 687-705.

Harnois, C., Demers, M. J., Bouchard, V., Vallée, K., Gagné, D., Fujita, N., Tsuruo, T., Vézina, A., Beaulieu, J. F., Côté, A. and Vachon, P. H. (2004) Human intestinal epithelial crypt cell survival and death: Complex modulations of Bcl-2 homologs by Fak, PI3-K/Akt-1, MEK/Erk, and p38 signaling pathways. J. Cell Physiol. 198, 209-222.

Heinrichsdorff, J., Luedde, T., Perdiguero, E., Nebreda, A. R. and Pasparakis, M. (2008) p38 alpha MAPK inhibits JNK activation and collaborates with IkappaB kinase 2 to prevent endotoxin-induced liver failure. EMBO Rep. 9, 1048-1054.

Hernández, M., Fuentes, L., Fernández Avilés, F. J., Crespo, M. S. and Nieto, M. L. (2002) Secretory phospholipase A2 elicits proinflammatory changes and upregulates the surface expression of fas ligand in monocytic cells: potential relevance for atherogenesis. Circ. Res. 90, 38-45.

Hetz, C. A., Hunn, M., Rojas, P., Torres, V., Leyton, L. and Quest, A. F. (2002) Caspase-dependent initiation of apoptosis and necrosis by the Fas receptor in lymphoid cells: onset of necrosis is associated with delayed ceramide increase. J. Cell Sci. 1, 4671-4683.

Hildeman, D. A., Zhu, Y., Mitchell, T. C., Kappler, J. and Marrack, P. (2002) Molecular mechanisms of activated T cell death in vivo. Curr. Opin. Immunol. 14, 354-359.

Hiraoka, M., Abe, A. and Shayman, J. A. (2002) Cloning and characterization of a lysosomal phospholipase A2, 1-O-acylceramide synthase. J. Biol. Chem. 277, 10090-10099.

Hiraoka, M., Abe, A. and Shayman, J. A. (2005) Structure and function of lysosomal phospholipase A2: identification of the catalytic triad and the role of cysteine residues. J. Lipid Res. 46: 2441-2447.

Holler, N., Zaru, R., Micheau, O., Thome, M., Attinger, A., Valitutti, S., Bodmer, J. L., Schneider, P., Seed, B. and Tschopp, J. (2000). Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule. Nat. Immunol. 1, 489-495.

Hsu, S. S., Huang, C. J., Cheng, H. H., Chou, C. T., Lee, H. Y., Wang, J. L., Chen, I. S., Liu, S. I., Lu, Y. C., Chang, H. T., Huang, J. K., Chen, J. S. and Jan, C. R. (2007) Anandamide-induced Ca2+ elevation leading to p38 MAPK phosphorylation and subsequent cell death via apoptosis in human osteosarcoma cells. Toxicology 231, 21-29.

Hsu, W. H., Hsieh, Y. S., Kuo, H. C., Teng, C. Y., Huang, H. I., Wang, C. J., Yang, S. F., Liou, Y. S. and Kuo, W. H. (2007) Berberine induces apoptosis in SW620 human colonic carcinoma cells through generation of reactive oxygen species and activation of JNK/p38 MAPK and FasL. Arch. Toxicol. 81, 719-728.

Hsu, Y. H., Burke, J. E., Stephens, D. L., Deems, R. A., Li, S., Asmus, K. M., Woods, Jr., V. L. and Dennis, E. A. (2008) Calcium binding rigidifies the C2 domain and the intra-domain interaction of GIVA phospholipase A2 as revealed by hydrogen/deuterium exchange mass spectrometry. J. Biol. Chem. 283, 9820-9827.

Hui, L., Bakiri, L., Mairhorfer, A., Schweifer, N., Haslinger, C., Kenner, L., Komnenovic, V., Scheuch, H., Beug, H. and Wagner, E. F. (2007) p38alpha suppresses normal and cancer cell proliferation by antagonizing the JNK-c-Jun pathway. Nat. Genet. 39, 741-749.

Ichijo, H. (1999) From receptors to stress-activated MAP kinases. Oncogene 18, 6087-6093.

Ivanov, V. N., Krasilnikov, M. and Ronai, Z. (2002) Regulation of Fas expression by STAT3 and c-Jun is mediated by phosphatidylinositol 3-kinase-AKT signaling. J. Biol. Chem. 277, 4932-4944.

Jaross, W., Eckey, R. and Menschikowski, M. (2002) Biological effects of secretory phospholipase A2 group IIA on lipoproteins and in atherogenesis. Eur. J. Clin. Investig. 32, 383-393.

Jia, L., Yu, W., Wang, P., Li, J., Sanders, B. G. and Kline, K. (2008) Critical roles for JNK, c-Jun, and Fas/FasL-Signaling in vitamin E analog-induced apoptosis in human prostate cancer cells. Prostate. 68, 427-441.

Kao, P. S., Chen, K. C., Lin, S. R. and Chang, L. S. (2008) The structural and functional contribution of N-terminal region and His-47 on Taiwan cobra phospholipase A2. J. Peptide Sci. 14, 342-348.

Karahashi, H., Nagata, K., Ishii, K. and Amano, F. (2000) A selective inhibitor of p38 MAP kinase, SB202190, induced apoptotic cell death of a lipopolysaccharide-treated macrophage-like cell line, J774.1. Biochim. Biophys. Acta. 1502, 207-223.

Karin, M., Liu, Z. and Zandi, E. (1997) AP-1 function and regulation. Curr. Opin. Cell Biol. 9, 240-246.

Kasibhatla, S., Brunner, T., Genestier, L., Echeverri, F., Mahboubi, A. and Green, D. R. (1998) DNA damaging agents induce expression of Fas ligand and subsequent apoptosis in T lymphocytes via the activation of NF-kappa B and AP-1. Mol. Cell. 1, 543-551.

Katsuki, H. and Okuda, S. (1995) Arachidonic acid as a neurotoxic and neurotrophic substance. Prog. Neurobiol. 46, 607-636.

Keesler, G. A., Bray, J., Hunt, J., Johnson, D. A., Gleason, T., Yao, Z., Wang, S.-W., Parker, C., Yamone, H., Cole, C. and Lichenstein, H. S. (1998) Purification and activation of recombinant p38 isoforms. Protein Expression Purif. 14, 221-228.

Kini, R. M. (1997) Venom Phospholipase A2 Enzymes. John Wiley & Sons, Chichester.

Kim, B. J., Ryu, S. W. and Song, B. J. (2006) JNK and p38 kinase-mediated phosphorylationof Bax leads to its activation and mitochondrial translocation and to apoptosisof human hepatoma HepG2 cells. J. Biol. Chem. 281, 21256-21265.

Kim, D. K., Rordorf, G., Nemenoff, R. A., Koroshetz, W. J. and Bonventre, J. V. (1995) Glutamate stably enhances the activity of two cytosolic forms of phospholipase A2 in brain cortical cultures. Biochem. J. 310, 83-90.

Kim, K. W., Choi, C. H., Kim, T. H., Kwon, C. H., Woo, J. S. and Kim, Y. K. (2009) Silibinin inhibits glioma cell proliferation via Ca2+/ROS/MAPK-dependent mechanism in vitro and glioma tumor growth in vivo. Neurochem. Res. 34, 1479-1490.

Kim, Y. E., Park, J. A., Nam, K. H., Kwon, H. J. and Lee, Y. (2009) Pyrrolidine dithiocarbamate-induced activation of ERK and increased expression of c-Fos in mouse embryonic stem cells. BMB Rep. 42, 148-153.

Kim, Y. S., Park, G. B., Lee, H. K., Song, H., Choi, I. H., Lee, W. J., Hur, D. Y. (2008) Cross-linking of B7-H1 on EBV-transformed B cells induces apoptosis through reactive oxygen species production, JNK signaling activation, and fasL expression. J. Immunol. 181, 6158-6169.

Koenig, W. and Khuseyinova, N. (2009) Lipoprotein-associated and secretory phospholipase A2 in cardiovascular disease: the epidemiological evidence. Cardiovasc. Drugs Ther. 23, 85-92.

Kolko, M., Rodriguez deTurco, E. B., Diemer, N. H. and Bazan, N. G. (2002) Secretory phospholipase A2-mediated neuronal cell death involves glutamate ionotropic receptors. Neuroreport 13, 1963-1966.

Kramer, R. M., Checani, G. C., Deykin, A., Pritzker, C. R. and Deykin, D. (1986) Solubilization and properties of Ca2+-dependent human platelet phospholipase A2. Biochim. Biophys. Acta. 878, 394-403.

Kramer, R. M., Roberts, E. F., Manetta, J. and Putnam, J. E. (1991) The Ca2+-sensitive cytosolic phospholipase A2 is a 100-kDa protein in human monoblast U937 cells. J. Biol. Chem. 266, 5268-5272.

Krishna, M. and Narang, H. (2008) The complexity of mitogen activated protein kinases (MAPKs) made simple. Cell. Mol. Life Sci. 65, 3525-3544.

Kuan, C. Y., Yang, D. D., Samanta Roy, D. R., Davis, R. J., Rakic, P. and Flavell, R. A. (1999) The Jnk1 and Jnk2 protein kinases are required for regional specific apoptosis during early brain development. Neuron 22, 667-676.

Kumar, S., McDonnell, P. C., Gum, R. J., Hand, A. T., Lee, J. C. and Young, P. R. (1997) Novel homologues of CSBP/p38 MAP kinase: activation, substrate specificity and sensitivity to inhibition by pyridinyl imidazoles. Biochem. Biophys. Res. Commun. 235, 533-538.

Kuwabara, M., Asanuma, T., Niwa, K. and Inanami, O. (2008) Regulation of cell survival and death signals induced by oxidative stress. J. Clin. Biochem. Nutr. 43, 51-57.

Kwon, K.J., Jung, Y.S., Lee, S.H., Moon, C.H. and Baik, E.J. (2005) Arachidonic acidinduces neuronal death through lipoxygenase and cytochrome P450 rather thancyclooxygenase. J. Neurosci. Res. 81, 73-84.

Kyriakis, J. M. and Avruch, J. (2001) Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. Physiol. Rev. 81, 807-869.

Lambeau, G. and Lazdunski, M. (1999) Receptors for a growing family of secreted phospholipases A2. Trends Pharmacol. Sci. 20, 162-170.

Lambeau, G. and Gelb, M. H. (2008) Biochemistry and physiology of mammalian secreted phospholipases A2. Annu. Rev. Biochem. 77, 495-520.

Lasham, A., Lindridge, E., Rudert, F., Onrust, R. and Watson, J. (2000) Regulation of the human fas promoter by YB-1, Puralpha and AP-1 transcription factors. Gene 252, 1-13.

Lauricella, M., Emanuele, S., D'Anneo, A., Calvaruso, G., Vassallo, B., Carlisi, D., Portanova, P., Vento, R. and Tesoriere, G. (2006) JNK and AP-1 mediate apoptosis induced by bortezomib in HepG2 cells via FasL/caspase-8 and mitochondria-dependent pathways. Apoptosis 11, 607-625.

Lavi, S., Herrmann, J., Lavi, R., McConnell, J. P., Lerman, L. O. and Lerman, A. (2008) Role of lipoprotein-associated phospholipase A2 in atherosclerosis. Curr. Atheroscler. Rep. 10, 230-235.

Lee, C., Park, D. W., Lee, J., Lee, T. I., Kim, Y. J., Lee, Y. S. and Baek, S. H. (2006) Secretory phospholipase A2 induces apoptosis through TNF-a and cytochrome c-mediated caspase cascade in murine macrophage RAW 264.7 cells. Eur. J. Pharmacol. 536, 47-53.

Lenardo, M. J. (1991) Interleukin-2 programs mouse αβ T lymphocytes for apoptosis. Nature 353, 858-861.

Lerman, A. and McConnell, J. P. (2008) Lipoprotein-associated phospholipase A2: a risk marker or a risk factor? Am. J. Cardiol. 101, 11-22.

Li, D., Ueta, E., Kimura, T., Yamamoto, T. and Osaki, T. (2004) Reactive oxygen species (ROS) control the expression of Bcl-2 family proteins by regulating their phosphorylation and ubiquitination. Cancer Sci. 95, 644-650.

Li, L., Chambard, J. C., Karin, M. and Olson, E. N. (1992) Fos and Jun repress transcriptional activation by myogenin and MyoD: the amino terminus of Jun can mediate repression. Genes Dev. 6, 676-689.

Li-Weber, M. and Krammer, P. H. (2003) Function and regulation of the CD95 (APO-1/Fas) ligand in the immune system. Semin. Immunol. 15, 145-157.

Li, X. R., Chong, A. S., Wu, J., Roebuck, K. A., Kumar, A., Parrillo, J. E., Rapp, U. R., Kimberly, R. P., Williams, J. W. and Xu, X. (1999) Transcriptional regulation of Fas gene expression by GA-binding protein and AP-1 in T cell antigen receptor.CD3 complex-stimulated T cells. J. Biol. Chem. 274, 35203-35210.

Lin, G., Noel, J., Loffredo, W., Stable, H. Z. and Tsai, M. D. (1988) Use of shortchain cyclopentano-phosphatidylcholines to probe the mode of activation of phospholipase A2 from bovine pancreas and bee venom. J. Biol. Chem. 263, 13208-13214.

Lin, T. N., Wang, Q., Simonyi, A., Chen, J. J., Cheung, W. M., He, Y. Y., Xu, J., Sun, A. Y., Hsu, C. Y. and Sun, G. Y. (2004) Induction of secretory phospholipase A2 in reactive astrocytes in response to transient focal cerebral ischemia in the rat brain. J. Neurochem. 90, 637-645.

Lipton, P. (1999) Ischemic cell death in brain neurons. Physiol. Rev. 79, 1431-1568.

Liu, L. and Rittenhouse, A.R. (2003) Arachidonic acid mediates muscarinic inhibition and enhancement of N-type Ca2+ current in sympathetic neurons. Proc. Natl. Acad.Sci. 100, 295-300.

Liu, W. H., Cheng, Y. C. and Chang, L. S. (2009) ROS-mediated p38 MAPK activation and ERK inactivation responsible for upregulation of Fas and FasL and autocrine Fas-mediated cell death in Taiwan cobra phospholipase A2-treated U937 cells. J. Cell Physiol. 219, 642-651.

Locksley, R. M., Killeen, N. and Lenardo, M. J. (2001) The TNF and TNF receptor superfamilies: integrating mammalian biology. Cell 104, 487-501.

Lopez-Vales, R., Navarro, X., Shimizu, T., Baskakis, C., Kokotos, G., Constantinou-Kokotou, V., Stephens, D., Dennis, E. A. and David, S. (2008) Intracellular phospholipase A2 group IVA and group VIA play important roles in Wallerian degeneration and axon regeneration after peripheral nerve injury. Brain 131, 2620-2631.

Ma, X. L., Kumar, S., Gao, F., Louden, C. S., Lopez, B. L., Christopher, T. A., Wang, C., Lee, J. C., Feuerstein, G. Z. and Yue, T. L. (1999) Inhibition of p38 mitogen-activated protein kinase decreases cardiomyocyte apoptosis and improves cardiac function after myocardial ischemia and reperfusion. Circulation 99, 1685-1691.

Manya, H., Aoki, J., Kato, H., Ishii, J., Hino, S., Arai, H. and Inoue, K. (1999) Biochemical characterization of various catalytic complexes of the brain platelet-activating factor acetylhydrolase. J. Biol. Chem. 274, 31827-31832.

Marambaud, P., Dreses-Werringloer, U. and Vingtdeux, V. (2009) Calcium signaling in neurodegeneration. Mol. Neurodegener. 6, 4-20.

Markland, F. S. (1998) Snake venoms and the hemostatic system. Toxicon 36, 1749-1800.

Mathisen, G. H., Thorkildsen, I. H. and Paulsen, R. E. (2007) Secretory PLA2-IIA and ROS generation in peripheral mitochondria are critical for neuronal death. Brain Res. 1153, 43-51.

Matsuzawa, A., Murakami, M., Atsumi, G., Imai, K., Prados, P., Inoue, K. and Kudo, I. (1996) Release of secretory phospholipase A2 from rat neuronal cells and its possible function in the regulation of catecholamine secretion. Biochem. J. 318, 701-709.

Matsukawa, J., Matsuzawa, A., Takeda, K. and Ichijo, H. (2004) The ASK1-MAP kinase cascades in mammalian stress response. J. Biochem. 136, 261-265.

McGahon, A., Bissonnette, R., Schmitt, M. Cotter, K. M. Green, D. R. and Cotter, T. G. (1994) BCR-ABL maintains resistance of chronic myelogenous leukemia cells to apoptotic cell death. Blood 83, 1179-1187.

McKew, J. C., Lee, K. L., Shen, M. W., Thakker, P., Foley, M. A., Behnke, M. L., Hu, B., Sum, F. W., Tam, S., Hu, Y., Chen, L., Kirincich, S. J., Michalak, R., Thomason, J., Ipek, M., Wu, K., Wooder, L., Ramarao, M. K., Murphy, E. A., Goodwin, D. G., Albert, L., Xu, X., Donahue, F., Ku, M. S., Keith, J., Nickerson-Nutter, C. L., Abraham, W. M., Williams, C., Hegen, M. and Clark, J. D. (2008) Indole cytosolic phospholipase A2 inhibitors: discovery and in vitro and in vivo characterization of 4-{3-[5-chloro-2-(2-{[(3,4-dichlorobenzyl) sulfonyl]amino}ethyl)-1-(diphenylmethyl)-1H-indol-3-yl]propyl} benzoic acid, efipladib. J. Med. Chem. 51, 3388-3413.

Meves, H. (1994) Modulation of ion channels by arachidonic acid. Prog. Neurobiol. 43, 175-186.

Mignen, O. and Shuttleworth, T. J. (2000) IARC, a novel arachidonate-regulated, noncapacitative Ca2+ entry channel. J. Biol. Chem. 275, 9114-9119.

Mignen, O., Thompson, J. L. and Shuttleworth, T. J. (2003) Ca2+ selectivity and fatty acid specificity of the noncapacitative, arachidonate-regulated Ca2+ (ARC) channels. J. Biol. Chem. 278, 10174-10181.

Min, J. H., Jain, M. K., Wilder, C., Paul, L., Apitz-Castro, R., Aspleaf, D. C. and Gelb, M. H. (1999) Membrane-bound plasma platelet activating factor acetylhydrolase acts on substrate in the aqueous phase. Biochemistry 38, 12935-12942.

Mishra, R. S., Carnevale, K. A. and Cathcart, M. K. (2008) iPLA2: front and center in human monocyte chemotaxis to MCP-1. J. Exp. Med. 205, 347-359.

Mohler 3rd, E. R., Ballantyne, C. M., Davidson, M. H., Hanefeld, M., Ruilope, L. M., Johnson, J. L. and Zalewski, A. (2008) The effect of darapladib on plasma lipoprotein-associated phospholipase A2 activity and cardiovascular biomarkers in patients with stable coronary heart disease or coronary heart disease risk equivalent: the results of a multicenter, randomized, double-blind, placebo-controlled study. J. Am. Coll. Cardiol. 51, 1632-1641.

Monje, P., Marinissen, M. J. and Gutkind, J. S. (2003) Phosphorylation of the carboxyl-terminal transactivation domain of c-Fos by extracellular signal-regulated kinase mediates the transcriptional activation of AP-1 and cellular transformation induced by platelet-derived growth factor. Mol. Cell Biol. 23, 7030-7043.

Monje, P., Hernández-Losa, J., Lyons, R. J., Castellone, M. D. and Gutkind, J. S. (2005) Regulation of the transcriptional activity of c-Fos by ERK. A novel role for the prolyl isomerase PIN1. J. Biol. Chem. 280, 35081-35084.

Montecucco, C., Gutiérrez, J. M. and Lomonte, B. (2008) Cellular pathology induced by snake venom phospholipase A2 myotoxins and neurotoxins: common aspects of their mechanisms of action. Cell Mol. Life Sci. 65, 2897-2912.

Moolenaar, W. H., vanMeeteren, L. A. and Giepmans, B. N. (2004) The ins and outs of lysophosphatidic acid signaling. Bioessays 26, 870-881.

Morsch, D. M., Carneiro, M. M., Lecke, S. B., Araújo, F. C., Camargos, A. F., Reis, F. M. and Spritzer, P. M. (2009) c-fos gene and protein expression in pelvic endometriosis: a local marker of estrogen action. J. Mol. Histol. 40, 53-58.

Moses, G. S. D., Jensen, M. D., Lue, L. F., Walker, D. G., Sun, A. Y., Simonyi, A. and Sun, G. Y. (2007) Secretory PLA2-IIA: A new inflammatory factor for Alzheimer’s disease. J. Neuroinflammation 3, 28-38.

Muniyappa, H. and Das, K. C. (2008) Activation of c-Jun N-terminal kinase (JNK) by widely used specific p38 MAPK inhibitors SB202190 and SB203580: a MLK-3-MKK7-dependent mechanism. Cell Signal. 20, 675-683.

Muthumani, K., Choo, A. Y., Hwang, D. S., Premkumar, A., Dayes, N. S., Harris, C., Green, D. R., Wadsworth, S. A., Siekierka, J. J. and Weiner, D. B. (2005) HIV-1 Nef-induced FasL induction and bystander killing requires p38 MAPK activation. Blood 106, 2059-2068.

Neidlinger, N. A., Larkin, S. K., Bhagat, A., Victorino, G. P. and Kuypers, F. A. (2006) Hydrolysis of phosphatidylserine-exposing red blood cells by secretory phospholipase A2 generates lysophosphatidic acid and results in vascular dysfunction. J. Biol. Chem. 281, 775-781.

Nevalainen, T. J., Eerola, L. I., Rintala, E., Laine, V. J., Lambeau, G. and Gelb, M. H. (2005) Time-resolved fluoroimmunoassays of the complete set of secreted phospholipases A2 in human serum. Biochim. Biophys. Acta. 1733, 210-223.

Niessen, H. W., Krijnen, P. A., Visser, C. A., Meijer, C. J. and Erik Hack, C. (2003) Type II secretory phospholipase A2 in cardiovascular disease: a mediator in atherosclerosis and ischemic damage to cardiomyocytes? Cardiovasc. Res. 60, 68-77.

Niquet, J., Seo, D. W. and Wasterlain, C. G. (2006) Mitochondrial pathways of neuronal necrosis. Biochem. Soc. Trans. 34, 1347-1351.

O’Connell, J., Houston, A., Bennett, M., O’Sullivan, G. and Shanahan, F. (2001) Immune privilege or inflammation? Insights into the Fas ligand enigma. Nat. Med. 7, 271-274.

Ogino, T., Ma, Y., Than, T. A., Omori, M. and Okada, S. (2000) Monochloramine enhances Fas (Apo-1/CD95) -induced apoptosis in Jurkat T cells. J. Leucok. Biol. 67, 46-52.

Ohgoh, M., Shimizu, H., Ogura, H. and Nishizawa, Y. (2000) Astroglial trophic support and neuronal cell death: Influence of cellular energy level on type of cell death induced by mitochondrial toxin in cultured rat cortical neurons. J. Neurochem. 75, 925-933.

Ohto, T., Uozumi, N., Hirabayashi, T. and Shimizu, T. (2005) Identification of novel cytosolic phospholipase A2s, murine cPLA2 which form a gene cluster with cPLA2. J. Biol. Chem., 280, 24576-24583.

Okazaki, K. and Sagata, N. (1995) The Mos/MAP kinase pathway stabilizes c-Fos by phosphorylation and augments its transforming activity in NIH 3T3 cells. EMBO J. 14, 5048-5059.

Olney, J. W. (2002) New insights and new issues in developmental neurotoxicology. Neurotoxicology 23, 659-668.

Ott, M., Gogvadze, V., Orrenius, S. and Zhivotovsky, B. (2007) Mitochondria, oxidative stress and cell death. Apoptosis 12, 913-922.

Ottmann, O. G., Druker, B. J., Sawyers, CL, Goldman, J. M., Reiffers, J., Silver, R. T., Tura, S., Fischer, T., Deininger, M. W., Schiffer, C. A., Baccarani, M., Gratwohl, A., Hochhaus, A., Hoelzer, D., Fernandes-Reese, S., Gathmann, I., Capdeville, R. and O'Brien, S. G. (2002) A phase 2 study of imatinib in patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoid leukemias. Blood
100, 1965-1971.

Park, M. T., Choi, J. A., Kim, M. J., Um, H. D., Bae, S., Kang, C. M., Cho, C. K., Kang, S., Chung, H. Y., Lee, Y. S. and Lee, S. J. (2003) Suppression of extracellular signal-related kinase and activation of p38 MAPK are two critical events leading to caspase-8- and mitochondria-mediated cell death in phytosphingosine-treated human cancer cells. J. Biol. Chem. 278, 50624-50634.

Pattingre, S., Bauvy, C., Carpentier, S., Levade, T., Levine, B. and Codogno, P. (2009) Role of JNK1-dependent Bcl-2 phosphorylation in ceramide-induced macroautophage. J. Biol. Chem. 284, 2719-2728.

Pender, M. P. (1999) Activation-induced apoptosis of autoreactive and alloreactive T lymphocytes in the target organ as a major mechanism of tolerance. Immunol. Cell Biol. 77, 216-223.

Penzo, D., Petronilli, V., Angelin, A., Cusan, C., Colonna, R., Scorrano, L., Pagano, F., Prato, M., Di Lisa, F. and Bernardi, P. (2004) Arachidonic acid released by phospholipase A2 activation triggers Ca2+-dependent apoptosis through the mitochondrial pathway. J. Biol. Chem. 279, 25219-25225.

Peter, M. E., Budd, R. C., Desbarats, J., Hedrick, S. M., Hueber, A. O., Newell, M. K., Owen, L. B., Pope, R. M., Tschopp, J., Wajant, H., Zörnig, M. and Lynch, D. H. (2007) The CD95 receptor: apoptosis revisited. Cell 129, 447-450.

Pickard, R. T., Strifler, B. A., Kramer, R. M. and Sharp, J. D. (1999) Molecular cloning of two new human paralogs of 85-kDa cytosolic phospholipase A2. J. Biol. Chem. 274, 8823-8831.

Plesniak, L. A., Yu, L. and Dennis, E. A. (1995) Conformation of micellar phospholipid bound to the active site of phospholipase A2. Biochemistry 34, 4943-4951.

Pompéia, C., Freitas, J. J. S., Kim, J. S., Zyngier, S. B. and Curi, R. (2002) Arachidonic acid cytotoxicity in leukocytes: implications of oxidative stress and eicosanoid synthesis. Biol. Cell 94, 251-265.

Pompéia, C., Lima, T. and Curi, R. (2003a) Arachidonic acid cytotoxicity: can arachidonic acid be a physiological mediator of cell death. Cell Biochem. Func. 21, 97-104.

Pompéia, C., Cury-Boaventura, M.F. and Curi, R. (2003b) Arachidonic acid triggers an oxidative burst in leukocytes. Braz. J. Med. Biol. Res. 36, 1549-1560.

Proskuryakov, S.Y., Konoplyannikov, A.G. and Gabai, V.L. (2003) Necrosis: a specific form of programmed cell death? Exp. Cell Res. 283, 1-16.

Punn, A., Mockridge, J. W., Farooqui, S., Marber, M. S. and Heads, R. J. (2000) Sustained activation of p42/p44 mitogen-activated protein kinase during recovery from simulated ischaemia mediates adaptive cytoprotection in cardiomyocytes. Biochem. J. 350, 891-899.

Ramanadham, S., Yarasheski, K. E., Silva, M. J., Wohltmann, M., Novack, D. V., Christiansen, B., Tu, X., Zhang, S., Lei, X. and Turk, J. (2008) Agerelated changes in bone morphology are accelerated in group VIA phospholipase A2 (iPLA2)-null mice. Am. J. Pathol. 172, 868-881.

Rao, N.G., Baas, A., Glasgow, W.C., Eling, T.E., Runge, M.S. and Alexander, R.W. (1994) Activation of mitogen-activated protein kinases by arachidonic acid and its metabolites in vascular smooth muscle cells. J. Biol. Chem. 269, 32586-32591.

Refaeli, Y., Von Parijs, L., London, C. A., Tschopp, J. and Abbas, A. K. (1998) Biochemical mechanisms of IL-2-regulated Fas-mediated T cell apoptosis. Immunity 8, 615-623.

Reynolds, L., Hughes, L., Louis, A. I., Kramer, R. A. and Dennis, E. A. (1993) Metal ion and salt effects on the phospholipase A2, lysophospholipase, and transacylase activities of human cytosolic phospholipase A2. Biochim. Biophys. Acta. 1167, 272-280.

Richmond, B. L., Boileau, A. C., Zheng, S., Huggins, K. W., Granholm, N. A., Tso, P and Hui, D. Y. (2001) Compensatory phospholipid digestion is required for cholesterol absorption in pancreatic phospholipase A2-deficient mice. Gastroenterology 120, 1193-1202.

Rizzo, M. T., Regazzi, E., Garau D, Akard, L., Dugan, M., Boswell, H. S., Rizzoli, V. and Carlo-Stella, C. (1999) Induction of apoptosis by arachidonic acid in chronic myeloid leukaemia cells. Cancer Res. 59, 5047-5053.

Rodriguez deTurco, E. B., Jackson, F. R., DeCoster, M. A., Kolko, M. and Bazan, N. G. (2002) Glutamate signalling and secretory phospholipase A2 modulate the release of arachidonic acid from neuronal membranes. J. Neurosci. Res. 68, 558-567.

Saegusa, J., Akakura, N., Wu, C. Y., Hoogland, C., Ma, Z., Lam, K. S., Liu, F. T., Takada, Y. K. and Takada, Y. (2008) Pro-inflammatory secretory phospholipase A2 type IIA binds to integrins avb3 and a4b1 and induces proliferation of monocytic cells in an integrin-dependent manner. J. Biol. Chem. 283, 26107-26115.

Safa, A. R., Day, T. W. and Wu, C. H. (2008) Cellular FLICE-like inhibitory protein (C-FLIP): a novel target for cancer therapy. Curr. Cancer Drug Targets 8, 37-46.

Sagi-Eisenberg, R. (2007) The mast cell: where endocytosis and regulated exocytosis meet. Immunol. Rev. 217, 292-303.

Schevitz, R. W., Bach, N. J., Carlson, D. G., Chirgadze, N. Y., Clawson, D. K., Dillard, R. D., Draheim, S. E., Hartley, L. W., Jones, N. D., Mihelich, E. D., Olkowski, J. L., Snyder, D. W., Sommers, C. and Wery, J. P. (1995) Structure-based design of the first potent and selective inhibitor of human non-pancreatic secretory phospholipase A2. Nat. Struct. Biol. 2, 458-465.

Schaloske, R. H. and Dennis, E. A. (2006) The phospholipase A2 superfamily and its group numbering system. Biochim. Biophys. Acta. 1761, 1246-1259.

Schapira, A. H. (1996) Oxidative stress and mitochondrial dysfunction in neurodegeneration. Curr. Opin. Neurol. 9, 260-264.

Scorrano, L., Penzo, D., Petronilli, V., Pagano, F. and Bernardi, P. (2001) Arachidonic acid causes cell death through the mitochondrial permeability transition. Implications for tumor necrosis factor-alpha aopototic signaling. J. Biol. Chem. 276, 12035-12040.

Scott, D. L., White, S. P., Otwinowski, Z., Yuan, W., Gelb, M. H. and Sigler, P. B. (1990) Interfacial catalysis: the mechanism of phospholipase A2. Science 250, 1541-1546.

Segura Torres, J. E., Chaparro-Huerta, V., Rivera Cervantres, M. C., Montes-González, R., Flores Soto, M. E. and Beas-Zárate, C. (2006) Neuronal cell death due to glutamate excitotocity is mediated by p38 activation in the rat cerebral cortex. Neurosci. Lett. 7, 233-238.

Seilhamer, J. J., Pruzanski, W., Vadas, P., Plant, S., Miller, J. A., Kloss, J., Johnson, L. K. (1989) Cloning and recombinant expression of phospholipase A2 present in rheumatoid arthritic synovial fluid. J. Biol. Chem. 264, 5335-5338.

Sergeeva, M., Strokin, M., Wang, H., Ubl, J. J. and Reiser, G. (2003) Arachidonic acid in astrocytes blocks Ca2+ oscillations by inhibiting store-operated Ca2+ entry, and causes delayed Ca2+ influx. Cell Calcium. 33, 283-292.

Serruys, P. W., Garcia-Garcia, H. M., Buszman, P., Erne, P., Verheye, S., Aschermann, M., Duckers, H., Bleie, O., Dudek, D., Botker, H. E., von Birgelen, C., D'Amico, D., Hutchinson, T., Zambanini, A., Mastik, F., van Es, G. A., van der Steen, A. F., Vince, D. G., Ganz, P., Hamm, C. W., Wijns, W. and Zalewski, A. (2008) Effects of the direct lipoprotein-associated phospholipase A2 inhibitor darapladib on human coronary atherosclerotic plaque. Circulation 118, 1172-1182.

Shea-Eaton, W., Sandhoff, T. W., Lopez, D., Hales, D. B. and McLean, M. P. (2002) Transcriptional repression of the rat steroidogenic acute regulatory (StAR) protein gene by the AP-1 family member c-Fos. Mol. Cell. Endocrinol. 188, 161-170.

Shin, D. H., Lee, E., Kim, H. J., Kim, S., Cho, S. S., Chang, K. Y. and Lee, W. J. (2002) Fas ligand mRNA expression in the mouse central nervous system. J. Neuroimmunol. 123, 50-57.

Simon, C., Simon, M., Vucelic, G., Hicks, M. J., Plinkert, P. K., Koitschev, A. and Zenner, H. P. (2001) The p38 SAPK pathway regulates the expression of the MMP-9 collagenase via AP-1-dependent promoter activation. Exp. Cell Res. 271, 344-355.

Singer, A. G., Ghomashchi, F., Le Calvez, C., Bollinger, J., Bezzine, S., Rouault, M., Sadilek, M., Nguyen, E., Lazdunski, M., Lambeau, G. and Gelb, M. H. (2002) Interfacial kinetic and binding properties of the complete set of human and mouse groups I, II, V, X, and XII secreted phospholipases A2. J. Biol. Chem. 277, 48535-48549.

Six, D. A. and Dennis, E. A. (2000) The expanding superfamily of phospholipase A2 enzymes: classification and characterization. Biochim. Biophys. Acta. 1488, 1-19.

Six, D. A. and Dennis, E. A. (2003) Essential Ca2+-independent role of the group IVA cytosolic phospholipase A2 C2 domain for interfacial activity. J. Biol. Chem. 278, 23842-23850.

Six, D. A., Barbayianni, E., Loukas, V., Constantinou-Kokotou, V., Hadjipavlou-Litina, D., Stephens, D., Wong, A. C., Magrioti, V., Moutevelis-Minakakis, P., Baker, S. F., Dennis, E. A. and Kokotos, G. (2007) Structure-activity relationship of 2-oxoamide inhibition of group IVA cytosolic phospholipaseA2 and group v secreted phospholipase A2. J. Med. Chem. 50, 4222-4235.

Song, C., Chang, X. J., Bean, K. M., Proia, M. S., Knopf, J. L. and Kriz, R. W. (1999) Molecular characterization of cytosolic phospholipase A2. J. Biol. Chem. 274, 17063-17067.

Song, H., Ramanadham, S., Bao, S., Hsu, F. F. and Turk, J. (2006) A bromoenol lactone suicide substrate inactivates group VIA phospholipase A2 by generating a diffusible bromomethyl keto acid that alkylates cysteine thiols. Biochemistry 45, 1061-1073.

Stafforini, D. (2009) Biology of platelet-activating factor acetylhydrolase (PAF-AH, lipoprotein associated phospholipase A2). Cardiovasc. Drugs Ther. 23, 73-83.

Stahelin, R. V., Subramanian, P., Vora, M., Cho, W. and Chalfant, C. E. (2007) Ceramide-1-phosphate binds group IVA cytosolic phospholipase A2 via a novel site in the C2 domain. J. Biol. Chem. 282, 20467-20474.

Stein, B., Yang, M. X., Young, D. B., Janknecht, Hunter, R., T., Murray, B. W. and Barbosa, M. S. (1997) p38-2, a novel mitogen-activated protein kinase with distinct properties. J. Biol. Chem. 272, 19509-19517.

Strand, S., Hofmann, W. J., Hug, H., Muller, M. and Otto, G. (1996) Lymphocyte apoptosis induced by CD95 (Apo-1/Fas) ligand-expressing tumor cells: A mechanism of immune evasion? Nature Med. 2, 1361-1366.

Su, X., Cheng, J., Liu, W., Liu, C., Wang, Z., Yang, P., Zhou, T. and Mountz, J. D. (1998) Autocrine and paracrine apoptosis are mediated by differential regulation of Fas ligand activity in two distinct Jurkat T cell populations. J. Immunol. 160, 5288-5293.

Sugino, T., Nozaki, K., Takagi, Y., Hattori, I., Hashimoto, N., Moriguchi, T. and Nishida, E. (2000) Activation of mitogen-activated protein kinases after transient forebrain ischemia in gerbil hippocampus. J. Neurosci. 20, 4506-4514.

Sun, G. Y., Xu, J., Jensen, M. D. and Simonyi, A. (2004) Phospholipase A2 in central nervous system: Implications for neurodegenerative diseases. J. Lipid Res. 45, 205-213.

Sun, G. Y., Xu, J., Jensen, M. D., Yu, S., Wood ,W. G., Gonzalez, F. A., Simonyi, A., Sun, A. Y. and Weisman, G. A. (2005) Phospholipase A2 in astrocytes: responses to oxidative stress, inflammation, and g protein-coupled receptor agonists. Mol. Neurobiol. 31, 27-42.

Sun, G. Y., Horrocks, L. A. and Farooqui, A. A. (2007) The roles of NADPH oxidase and phospholipases A2 in oxidative and inflammatory responses in neurodegenerative diseases. J. Neurochem. 103, 1-16.

Surette, M. E., Fonteh, A. N., Bernatchez, C. and Chilton, F. H. (1999) Perturbations in the control of cellular arachidonic acid levels block cell growth and induce apoptosis in HL-60 cells. Carcinogenesis 20, 757-763.

Teixeira, C. F., Landucci, E. C., Antunes, E., Chacur, M. and Cury, Y. (2003) Inflammatory effects of snake venom myotoxic phospholipases A2. Toxicon 42, 947-962.

Tezel, G. (2006) Oxidative stress in glaucomatous neurodegeneration: mechanisms and consequences. Prog. Retin. Eye Res. 25, 490-513.

Thwin, M. M., Ong, W. Y., Fong, C. W., Sato, K., Kodama, K., Farooqui, A. A. and Gopalakrishnakone, P. (2003) Secretory phospholipase A2 activity in the normal and kainate injected rat brain, and inhibition by a peptide derived from python serum. Exp. Brain Res. 150, 427-433.

Tjoelker, L. W., Eberhardt, C., Unger, J., Trong, H. L., Zimmerman, G. A., McIntyre TM, Stafforini, D. M., Prescott, S. M. and Gray, P. W. (1995a) Plasma platelet-activating factor acetylhydrolase is a secreted phospholipase A2 with a catalytic triad. J. Biol. Chem. 270, 25481-25487.

Tjoelker LW, Wilder C, Eberhardt C, Stafforini DM, Dietsch G, Schimpf B, Hooper, S., Trong, H. L., Cousens, L. S., Zimmerman, G. A., Yamadat, Y., Mclntyre, T. M., Prescott, S. M. and Gray, P. W. (1995b) Anti-inflammatory properties of a plateletactivating factor acetylhydrolase. Nature 374, 549-553.

Toborek, M., Malecki, A., Garrido, R., Mattson, M. P., Hennig, B. and Young, B. (1999) Arachidonic acid-induced oxidative injury to cultured spinal cord neurons. J. Neurochem. 73, 684-692.

Tourian, L. Jr., Zhao, H. and Srikant, C. B. (2004) p38alpha, but not p38beta, inhibits the phosphorylation and presence of c-FLIPS in DISC to potentiate Fas-mediated caspase-8 activation and type I apoptotic signaling. J. Cell Sci. 117, 6459-6471.

Tsai, I. H., Wu, S. H. and Lo, T. B. (1981) Complete amino acid sequence of a phospholipase A2 from the venom of Naja naja atra (Taiwan cobra). Toxicon 19, 141-152.

Ueda, S., Masutani, H., Nakamura, H., Tanaka, T., Ueno, M. and Yodoi, J. (2002) Redox control of cell death. Antioxid. Redox Signal. 4, 405-414.

Ugolini, G., Raoul, C., Ferri, A., Haenggeli, C., Yamamoto, Y., Salaun, D., Henderson, C. E., Kato, A. C., Pettmann, B. and Hueber, A. O. (2003) Fas/tumor necrosis factor receptor death signaling is required for axotomy-induced death of motoneurons in vivo. J. Neurosci. 23, 8526-8531.

Uozumi, N., Kume, K., Nagase, T., Nakatani, N., Ishii, S., Tashiro, F., Komagata, Y., Maki, K., Ikuta, K., Ouchi, Y., Miyazaki, J. and Shimizu, T. (1997) Role of cytosolic phospholipase A2 in allergic response and parturition. Nature 390, 618-622.

Uozumi, N. and Shimizu, T. (2002) Roles for cytosolic phospholipase A2 as revealed by gene-targeted mice. Prostaglandins Other Lipid Mediat. 68-69, 59-69.

Vercammen, D., Beyaert, R., Denecker, G., Goossens, V., van Loo, G., Declercq, W., Grooten, J., Fiers, W. and Vandenabeele, P. (1998a). Inhibition of caspases increases the sensitivity of L929 cells to necrosis mediated by tumor necrosis factor. J. Exp. Med. 187, 1477-1485.

Vercammen, D., Brouckaert, G., Denecker, G., van de Craen, M., Declercq, W., Fiers, W. and Vandenabeele, P. (1998b). Dual signaling of the Fas receptor: initiation of both apoptotic and necrotic cell death pathways. J. Exp. Med. 188, 919-930.

Verheij, H. M., Slotboom, A. J. and de Haas, G. H. (1981) Structure and function of phospholipase A2. Rev. Physiol. Biochem. Pharmacol. 91, 191-203.

Villena, J., Henriquez, M., Torres, V., Moraga, F., Díaz-Elizondo, J., Arredondo, C., Chiong, M., Olea-Azar, C., Stutzin, A., Lavandero, S. and Quest, A. F. (2008) Ceramide-induced formation of ROS and ATP depletion trigger necrosis in lymphoid cells. Free Radic. Biol. Med. 15, 1146-1160.

Walker, P. R., Saas, P. and Dietrich, P. Y. (1997) Role of Fas ligand (CD95L) in immune escape: The tumor cell strikes back. J. Immunol. 158, 4521-4524.

Wallach, D., Varfolomeev, E. E., Malinin, N. L., Goltsev, Y. V., Kovalenko, A.V. and Boldin, M. P. (1999) Tumor necrosis factor receptor and Fas signaling mechanisms. Annu. Rev. Immunol. 17, 331-367.

Wang, C. X. and Shuaib, A. (2002) Involvement of inflammatory cytokines in central nervous system injury. Prog. Neurobiol. 67, 161-172.

Wang, X. (2001) The expanding role of mitochondria in apoptosis. Genes Dev. 15, 2922-2933.

Wang, Z. Q., Ovitt, C., Grigoriadis, A. E., Mohle-Steinlein, U., Ruther, U. and Wagner, E. F. (1992) Bone and haematopoietic defects in mice lacking c-fos. Nature 360, 741-745.

Weber, C. H. and Vincenz, C. (2001) The death domain superfamily: a tale of two interfaces? Trends Biochem. Sci. 26, 475-481.

Wei, Y., Sinha, S. and Levine, B. (2008) Dual role of JNK1-mediated phosphorylation of Bcl-2 in autophagy and apoptosis regulation. Autophagy 4, 949-951.

White, S. P., Scott, D. L., Otwinowski, Z., Gelb, M. H. and Sigler, P. B. (1990) Crystal structure of cobra-venom phospholipase A2 in a complex with a transition-state analogue. Science 250, 1560-1563.

Winstead, M. V., Balsinde, J. and Dennis, E. A. (2000) Calcium independent phospholipase A2: structure and function. Biochim. Biophys. Acta. 1488, 28-39.

Wu, D. and Cederbaum, A. I. (2003) Role of p38 MAPK in CYP2E1-dependent arachidonic acid toxicity. J. Biol. Chem. 278, 1115-1124.

Xia, Z., Dickens, M., Raingeaud, J., Davis, R. J. and Greenberg, M. E. (1995) Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Science 270, 1326-1331.

Yagami, T., Ueda, K., Asakura, K., Hayasaki-Kajiwara, Y., Nakazato, T., Sakaeda, T., Hata, S., Kuroda, K., Takasu, N. and Hori, Y. (2002a) Group IB secretory phospholipase A induces neuronal cell death via apoptosis. J. Neurochem. 81, 449-461.

Yagami, T., Ueda, K., Asakura, K., Hata, S., Kuroda, T., Sakaeda, T., Takasu, N., Tanaka, K., Gemba, T. and Hori, Y. (2002b) Human group IIA secretory phospholipase A induces neuronal cell death via apoptosis. Mol. Pharmacol. 61, 114-126.

Yagami, T., Ueda, K., Asakura, K., Sakaeda, T., Hata, S., Kuroda, T., Sakaguchi, G., Itoh, N., Hashimoto, Y. and Hori, Y. (2003a) Porcine pancreatic group IB secretory phospholipase A2 potentiates Ca2+ influx through L-type voltage-sensitive Ca2+ channels. Brain Res. 960, 71-80.

Yagami, T., Ueda, K., Asakura, K., Sakaeda, T., Nakazato, H., Hata, S., Kuroda, T., Sakaguchi, G., Itoh, N., Hashimoto, Y. and Hori, Y. (2003b) Human group IIA secretory phospholipase A potentiates Ca2+ influx through L-type voltagesensitive Ca2+ channel. J. Neurochem. 85, 749-758.

Yaksh, T. L., Kokotos, G., Svensson, C. I., Stephens, D., Kokotos, C. G., Fitzsimmons, B., Hadjipavlou-Litina, D., Hua, X. Y. and Dennis, E. A. (2006) Systemic and intrathecal effects of a novel series of phospholipaseA2 inhibitors on hyperalgesia and spinal prostaglandin E-2 release. J. Pharmacol. Exp. Ther. 316, 466-475.

Yan, Y., Wei, C. L., Zhang, W. R., Cheng, H. P. and Liu, J. Cross-talk between calcium and reactive oxygen species signaling. Acta. Pharmacol. Sin. 27, 821-826.

Yang, C. C., King, K. and Sun, T. P. (1981) Chemical modification of lysine and histidine residues in phospholipase A2 from the venom of Naja naja atra (Taiwan cobra). Toxicon 19, 645-659.

Yang, C. C. and Chang, L. S. (1984) Tryptophan modification of phospholipase A2 enzymes and presynaptic neurotoxins from snake venom. J. Protein Chem. 3, 195-213.

Yang, C. C. and Chang, L. S. (1988) Role of the N-terminal region in phospholipases A2 from Naja naja atra (Taiwan cobra) and Naja nigricollis (spitting cobra) venoms. Toxicon 26, 721-731.

Yang, C. C. and Chang, L. S. (1989a) Studies on the status of lysine residues in phospholipase A2 from Naja naja atra (Taiwan cobra) snake venom. Biochem. J. 262, 855-860.

Yang, C.C. and Chang, L.S. (1989b) Assessment of the role of tryptophan residues in phospholipase A2 by fluorescence quenching. Int. J. Biol. Macromol. 11, 13-16.

Yang, S. H., Chien, C. M., Lu, C. M., Chen, Y. L., Chang, L. S. and Lin, S. R. (2007) Involvement of c-Jun N-terminal kinase in G2/M arrest and FasL-mediated apoptosis induced by a novel indoloquinoline derivative, IQDMA, in K562 cells. Leuk. Res. 31, 1413-1420.

Yoshizumi, K., Liu, S. Y., Miyata, T., Saita, S., Ohno, M., Iwanaga, S. and Kihara, H. (1990) Purification and amino acid sequence of basic protein I, a lysine-49-phospholipase A2 with low activity, from the venom of Trimeresurus flavoviridis (Habu snake).Toxicon 28, 43-54.

Yu, L. and Dennis, E. A. (1991) Critical role of a hydrogen bond in the interaction of phospholipase A2 with transition-state and substrate analogues. Proc. Natl. Acad. Sci. USA. 88, 9325-9329.

Yuan, L. Q., Liu, Y. S., Luo, X. H., Guo, L. J., Xie, H., Lu, Y., Wu, X. P. and Liao, E. Y. (2008) Recombinant tissue metalloproteinase inhibitor-3 protein induces apoptosis of murine osteoblast MC3T3-E1. Amino Acids 35, 123-127.

Yue, T. L., Wang, C., Gu, J. L., Ma, X. L., Kumar, S., Lee, J. C., Feuerstein, G. Z., Thomas, H., Maleeff, B. and Ohlstein, E. H. (2000) Inhibition of extracellular signal-regulated kinase enhances ischemia/reoxygenation-induced apoptosis in cultured cardiac myocytes and exaggerates reperfusion injury in isolated perfused heart. Circ. Res. 86, 692-699.

Zhang, X., Shan, P., Alam, J., Davis, R. J., Flavell, R. A. and Lee, P. J. (2003) Carbon monoxide modulates Fas/Fas ligand, caspases, and Bcl-2 family proteins via the p38alpha mitogen-activated protein kinase pathway during ischemia-reperfusion lung injury. J. Biol. Chem. 278, 22061-22070.

Zong, W. X. and Thompson, C.B. (2006) Necrotic death as a cell fate. Genes Dev. 20, 1-15.

Zuliani, C., Kleber, S., Klussmann, S., Wenger, T., Kenzelmann, M., Schreglmann, N., Martinez, A., del Rio, J. A., Soriano, E., Vodrazka, P., Kuner, R., Groene, H. J., Herr, I., Krammer, P. H. and Martin-Villalba, A. (2006) Control of neuronal branching by the death receptor CD95 (Fas/Apo-1). Cell Death. Differ. 13, 31-40.