Stress signaling of apoptosis via ceramide and c-jun kinase

Abstract

Mammalian systems respond to environmental stress by either adapting for survival or undergoing programmed cell death (apoptosis). While it is generally believed that the caspase family of proteases are essential effectors of the apoptotic response, much less is clear about the signaling machinery required to activate the caspase system in response to stress stimuli. In the past few years, increasing evidence has linked the sphingomyelin and c-jun kinase (JNK) pathways to the death response in various cellular systems. Both signaling pathways are evolutionarily conserved through yeast. Since yeast does not undergo apoptosis, these pathways appear evolutionarily older than the caspase-mediated death programs. This paper reviews the role of sphingomyelin/ceramide and the JNK pathways in co-ordinating the signaling events leading to apoptosis.

References

Spiegel S. , Foster D. , Kolesnick R. Signal transduction through lipid second messengers. Curr Opin Cell Biol 1996; 8: 159—167.

Hannun YA Functions of ceramide in coordinating cellular responses to stress. Science 1996; 274: 1855—1859.

Kolesnick RN Sphingomyelin and derivatives as cellular signals . Prog Lipid Res 1991; 30: 1—38.

Tomiuk S. , Hofmann K. , Nix M. , Zumbansen M. , Stoffel W.

Cloned mammalian neutral sphingomyelinase: functions in sphingolipid signaling?

Proc Natl Acad Sci USA 1998; 95: 3638—3643.

Schissel SL , Jiang XC , Tweedie-Hardman J. et al. Secretory sphingomyelinase, a product of the acid sphingomyelinase gene, can hydrolyze atherogenic lipoproteins at neutral pH. Implications for atherosclerotic lesion development. J Biol Chem 1998; 273: 2738—2746.

Marathe S. , Schissel SL , Yellin MJ et al. Human vascular endothelial cells are a rich and regulatable source of secretory sphingomyelinase. Implications for early atherogenesis and ceramide-mediated cell signaling. J Biol Chem 1998; 273: 4081—4088.

Liu,P. , Ying Y. , Ko YG , Anderson Rgw. Localization of platelet-derived growth factor-stimulated phosphorylation cascade to caveolae. J Biol Chem 1996; 271: 10299—10303.

Bilderback TR , Grigsby RJ , Dobrowsky RT Association of p75(NTR) with caveolin and localization ofneurotrophininduced sphingomyelin hydrolysis to caveolae. J Biol Chem 1997; 272: 10922—10927.

Jarvis WD , Grant S. , Kolesnick RN Ceramide and the induction of apoptosis. Clin Cancer Res 1996; 2: 1—6.

10.

Verheij M. , Bose R. , Lin XH et al. Requirement for ceramide-initiated SAPK/JNK signalling in stress-induced apoptosis. Nature 1996; 380: 75—79.

11.

Hannun YA , Obeid LM Ceramide and the eukaryotic stress response. Biochem Soc Trans 1997; 25: 1171—1175.

12.

Pena LA , Fuks Z. , Kolesnick R. Stress-induced apoptosis and the sphingomyelin pathway. Biochem Pharmacol 1997; 53: 615—621.

13.

Santana P. , Peña LA , Haimovitz-Friedman A. et al. Acid sphingomyelinase-deficient human lymphoblasts and mice are defective in radiation-induced apoptosis. Cell 1996; 86: 189—199.

14.

Haimovitz-Friedman A. , Cordon-Cardo C. , Bayoumy S. et al. Lipopolysaccharide induces disseminated endothelial apoptosis requiring ceramide generation. J Exp Med 1997; 186: 1831—1841.

15.

Wiegmann K. , Schutze S. , Machleidt T. , Witte D. , Kronke M. Functional dichotomy of neutral and acidic sphingomyelinases in tumor necrosis factor signaling. Cell 1994; 78: 1005—1015.

16.

Chinnaiyan AM , Tepper CG , Seldin MF et al. FADD/MORT1 is a common mediator of CD95 (Fas/APO-1) and tumor necrosis factor receptor-induced apoptosis. J Biol Chem 1996; 271: 4961—4965.

17.

Schwandner R. , Wiegmann K. , Bernardo K. , Kreder D. , Krönke M. TNF receptor death domain-associated proteins TRADD and FADD signal activation of acid sphingomyelinase. J Biol Chem 1998; 273: 5916—5922.

18.

Wiegmann K. , Schwandner R. , Krut O. , Yeh WC , Mak TW , Krönke M. Requirement of FADD for tumor necrosis factor-induced activation of acid sphingomyelinase. J Biol Chem 1999; 274: 5267—5270.

19.

Adam-Klages S. , Adam D. , Wiegmann K. et al. FAN, a novel WDrepeat protein, couples the p55 TNF-receptor to neutral sphingomyelinase. Cell 1996; 86: 937—947.

20.

Adam D. , Wiegmann K. , Adam-Klages S. , Ruff A. , Krönke M. A novel cytoplasmic domain of the p55 tumor necrosis factor receptor initiates the neutral sphingomyelinase pathway. J Biol Chem 1996; 271: 14617—14622.

21.

Kreder D. , Krut O. , Adam-Klages S. et al. Impaired neutral sphingomyelinase activation and cutaneous barrier repair in FAN-deficient mice. EMBO J 1999; 18: 2472—2479.

22.

Hildt E. , Oess S. Identification of grb2 as a novel binding partner of tumor necrosis factor (TNF) receptor I. J Exp Med 1999; 189: 1707—1714.

23.

Dbaibo GS , Perry DK , Gamard CJ et al. Cytokine response modifier A (CrmA) inhibits ceramide formation in response to tumor necrosis factor (TNF-alpha) CrmA and Bcl-2 target distinct components in the apoptotic pathway. J Exp Med 1997; 185: 481—490.

24.

Liu B. , Hannun YA Inhibition of the neutral magnesium-dependent sphingomyelinase by glutathione . J Biol Chem 1997; 272: 16281—16287.

25.

Liu B. , Andrieu-Abadie N. , Levade T. , Zhang P. , Obeid LM , Hannun YA Glutathione regulation of neutral sphingomyelinase in tumor necrosis factor-induced cell death. J Biol Chem 1998; 273: 11313—11320.

26.

Tepper AD , Boesen-de Cock Jgr , Borst Evj , van Blitterswijk VJ CD95/Fas-induced ceramide formation proceeds with slow kinetics and is not blocked by caspase-3/CPP32 inhibition. J Biol Chem 1997; 272: 24308—24312.

27.

Boesen-de Cock Jgr , Tepper AD , van Blitterswijk Evwj , Jannie Borst J. CD95 (Fas/APO-1) induces ceramide formation and apoptosis in the absence of a functional acid sphingomyelinase. J Biol Chem 1998; 273: 7560—7565.

28.

Brenner B. , Ferlinz K. , Grassme H. et al. Fas/CD95/Apo-I activates the acidic sphingomyelinase via caspases . Cell Death Differ 1998; 5: 29—37.

29.

De Maria R , Rippo MR , Schuchman EH , Testi R. Acidic sphingomyelinase (ASM) is necessary for Fas-induced GD3 ganglioside accumulation and efficient apoptosis of lymphoid cells. J Exp Med 1998; 187: 897—902.

30.

Tepper AD , de Vries E. , van Blitterswijk WJ , Borst J. Ordering of ceramide formation, caspase activation, and mitochondrial changes during CD95- and DNA damage—induced apoptosis . J Clin Invest 1999; 103: 971—978.

31.

Laethem RM , Hannun YA , Jayadev S. et al. Increases in neutral, Mg2+-dependent and acidic, Mg2+-independent sphingomyelinase activities precede commitment to apoptosis and are not a consequence of caspase 3-like activity in Molt-4 cells in response to thymidylate synthase inhibition by GW1843. Blood 1998; 91: 4350—4360.

32.

Chen L. , Kim TJ , Pillai S. Inhibition of caspase activity prevents anti-IgM induced apoptosis but not ceramide generation in WEHI 231 B cells. Mol Immunol 1998; 35: 195—205.

33.

Yoshimura S. , Banno Y. , Nakashima S. et al. Ceramide formation leads to caspase-3 activation during hypoxic PC12 cell death. Inhibitory effects of bcl-2 on ceramide formation and caspase-3 activation. J Biol Chem 1998; 273: 6921—6927.

34.

Cifone MG , Migliorati G. , Parroni R. et al. Dexamethasone-induced thymocyte apoptosis: apoptotic signal involves the sequential activation of phosphoinositide-specific phospholipase C, acidic sphingomyelinase, and caspases. Blood 1999; 93: 2282—2296.

35.

Jaffrezou JP , Levade T. , Bettaieb A. et al. Daunorubicin-induced apoptosis: triggering of ceramide generation through sphingomyelin hydrolysis. EMBO J 1996 ; 15: 2417—2424.

36.

Haimovitz-Friedman A. , Kan CC , Ehleiter D. et al. Ionizing radiation acts on cellular membranes to generate ceramide and initiate apoptosis. J Exp Med 1994; 180: 525—535.

37.

Goldkorn T. , Balaban N. , Shannon M. et al. H 2O2 acts on cellular membranes to generate ceramide signaling and initiate apoptosis in tracheobronchial epithelial cells. J Cell Sci 1998; 111: 3209—3220.

38.

Herr I. , Wilhelm D. , Böhler T. , Angel P. , Debatin KM Activation of CD95 (APO-1/Fas) signaling by ceramide mediates cancer therapy-induced apoptosis. EMBO J 1997; 16: 6200—6208.

39.

Herr I. , Martin-Villalba A. , Kurz E. et al. FK506 prevents stroke-induced generation of ceramide and apoptosis signaling. Brain Res 1999; 826: 210—219.

40.

Susin SA , Zamzami N. , Castedo M. et al. The central executioner of apoptosis: multiple connections between protease activation and mitochondria in Fas/APO-1/CD95- and ceramide-induced apoptosis. J Exp Med 1997; 186: 25—37.

41.

Whitmarsh AJ , Davis RJ Transcription factor AP-1 regulation by mitogen-activated protein kinase signal transduction pathways. J Mol Med 1996; 74: 589—607.

42.

Ip YT , Davis RJ Signal transduction by the c-Jun N-terminal kinase (JNK) — from inflammation to development. Curr Opin Cell Biol 1998; 10: 205—219.

43.

Fanger GR , Gerwins P. , Widmann C. , Jarpe MB , Johnson GL MEKKs, GCKs, MLKs, PAKs, TAKs, and TPLs: upstream regulators of the c-Jun amino-terminal kinases?.Curr Opin Genet Dev 1997; 7: 67—74.

44.

Sanna MG , Duckett CS , Richter Bwm , Thompson CB , Ulevitch RJ Selective activation of JNK1 is necessary for the anti-apoptotic activity of hILP. Proc Natl Acad Sci USA 1998; 95: 6015—6020.

45.

Rothe M. , Pan MG , Henzel WJ , Ayres TM , Goeddel DV The TNFR2-TRAF signaling complex contains two novel proteins related to baculoviral inhibitor of apoptosis proteins. Cell 1995 ; 83: 1243—1252.

46.

Duckett CS , Nava VE , Gedrich RW et al. A conserved family of cellular genes related to the baculovirus IAP gene and encoding apoptosis inhibitors. EMBO J 1996; 15: 2685—2694.

47.

Liston P. , Roy N. , Tamai K. et al. Suppression of apoptosis in mammalian cells by NAIP and a related family of IAP genes. Nature 1996; 379: 349—353.

48.

Nishina H. , Vaz C. , Billia P. et al. Defective liver formation and liver cell apoptosis in mice lacking the stress signaling kinase SEK1/MKK4. Development 1999; 126: 505—516.

49.

Kyriakis JM , Avruch J. Sounding the alarm: protein kinase cascades activated by stress and inflammation. J Biol Chem 1996; 271: 24313—24316.

50.

Atfi A. , Buisine M. , Mazars A. , Gespach C. Induction of apoptosis by DPC4, a transcriptional factor regulated by transforming growth factor through stress-activated protein kinase/c-jun N-terminal kinase (SAPK/JNK) signaling pathway. J Biol Chem 1997; 272: 24731—24734.

51.

Brenner B. , Koppenhoefer U. , Weinstock C. , Linderkamp O. , Lang F. , Gulbins E. Fas- or ceramide-induced apoptosis is mediated by a Rac1-regulated activation of Jun N-terminal kinase/p38 kinases and GADD153. J Biol Chem 1997; 272: 22173—22181.

52.

Butterfield L. , Storey B. , Maas L. , Heasley LE c-Jun NH2-terminal kinase regulation of the apoptotic response of small cell lung cancer cells to ultraviolet radiation . J Biol Chem 1997; 272: 10110—10116.

53.

Cardone MH , Salvesen GS , Widmann C. , Johnson G. , Frisch SM The regulation of anoikis: MEKK-1 activation requires cleavage by caspases . Cell 1997; 90: 315—323.

54.

Chuang TH , Hahn KM , Lee JD , Danley DE , Bokoch GM The small GTPase Cdc42 initiates an apoptotic signaling pathway in Jurkat T lymphocytes. Mol Biol Cell 1997; 8: 1687—1698.

55.

Goillot E. , Raingeaud J. , Ranger A. et al. Mitogen-activated protein kinase-mediated Fas apoptotic signaling pathway. Proc Natl Acad Sci USA 1997; 94: 3302—3307.

56.

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.

57.

Dickens M. , Rogers JS , Cavanagh J. et al. A cytoplasmic inhibitor of the JNK signal transduction pathway . Science 1997; 277: 693—696.

58.

Kuan CY , Yang DD , Roy Drs , Davis RJ , Rakic P. , Flavell RA The Jnk1 and Jnk2 protein kinases are required for regional specific apoptosis during early brain development. Neuron 1999 ; 22: 667—676.

59.

Sabapathy K. , Hu Y. , Kallunki T. et al. JNK 2 is required for efficient T-cell activation and apoptosis but not for normal lymphocyte development. Curr Biol 1999; 9: 116—125.

60.

Yang DD , Kuan CY , Whitmarsh AJ et al. Absence of excitotoxicity-induced apoptosis in the hippocampus of mice lacking the Jnk3 gene. Nature 1997 ; 389: 865—870.

61.

Ichijo H. , Nishida E. , Irie K. et al. Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways. Science 1997; 275: 90—94.

62.

Yang X. , Khosravi-Far R. , Chang HY , Baltimore D. Daxx, a novel Fas-binding protein that activates JNK and apoptosis. Cell 1997; 89: 1067—1076.

63.

Yeh WC , Shahinian A. , Speiser D. et al. Early lethality, functional NF-kappaB activation, and increased sensitivity to TNF-induced cell death in TRAF2-deficient mice. Immunity 1997; 7: 715—725.

64.

Shirakabe K. , Yamaguchi K. , Shibuya H. et al. TAK1 mediates the ceramide signaling to stress-activated protein kinase/c-Jun N-terminal kinase. J Biol Chem 1997; 272: 8141—8144.

65.

Huang C. , Ma W. , Ding M. , Bowden GT , Dong Z. Direct evidence for an important role of sphingomyelinase in ultraviolet-induced activation of c-Jun N-terminal kinase. J Biol Chem 1997; 272: 27753—27757.

66.

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

67.

Chen YR , Wang X. , Templeton D. , Davis RJ , Tan TH The role of c-Jun N-terminal kinase (JNK) in apoptosis induced by ultraviolet C and gamma radiation. Duration of JNK activation may determine cell death and proliferation. J Biol Chem 1996; 271: 31929—31936.

68.

Gajate C. , Santos-Beneit A. , Modolell M. , Mollinedo F. Involvement of c-jun NH2-termianal kinase activation and c-Jun in the induction of apoptosis by the ether phospholipid 1-o-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine . Mol Pharmacol 1998; 53: 602—612.

69.

Maundrell K. , Antonsson B. , Magnenat E. et al. Bcl-2 undergoes phosphorylation by c-Jun N-terminal kinase/stress-activated protein kinases in the presence of the constitutively active GTPbinding protein Rac1 .J Biol Chem 1997; 272: 25238—25242.