转化生长因子-β1抗细胞凋亡的信号传导机制
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摘要
血清缺失诱导NIH3T3细胞凋亡，并伴有内源性神经酰胺的生成增加和p38有丝分裂原活化蛋白激酶(MAP激酶)的活化。用转化生长因子-β1(TGF-β1)处理细胞激活了胞外信号调节激酶1和2(ERK1/ERK2)，抑制了血清缺失诱导的p38 MAP激酶的活化以及内源性神经酰胺的生成增加，从而刺激细胞的增殖，阻止细胞的凋亡。用SB203580抑制p38 MAP激酶能显著降低血清缺失诱导的细胞凋亡。p38超量表达能增强细胞凋亡并降低TGF-β1的抗凋亡效应。用PD98059抑制ERK1/ERK2能彻底抑制TGF-β1诱导的细胞增殖，并且能部分抑制TGF-β1的抗凋亡作用。SB203580和PD98059对TGF-β1介导的对神经酰胺生成的抑制都没有显著的效应。血清缺失引起的NIH3T3细胞的凋亡也能被广谱性的切冬酶(caspase)抑制剂所抑制，TGF-β1能抑制切冬酶的活性。我们的结果显示神经酰胺、p38和ERK1/ERK2在细胞增殖和刺激诱导的细胞凋亡中起着关键但截然不同的作用。TGF-β1通过对复杂的信号传递事件的完全不同的影响，包括活化ERK1/ERK2、抑制p38的活化和神经酰胺的生成增加，而抑制血清缺失诱导的细胞凋亡。
Serum deprivation induces apoptosis in NIH3T3 cells, which is associated with increased intracellular ceramide generation and with the activation of p38 mitogen-activated protein (MAP) kinase. Treatment of cells with transforming growth factor-β1 (TGF-β1) activated the extracellular signal regulated kinase 1 and 2 (ERK1/ERK2), inhibited the serum deprivation-induced p38 activation and the increase in intracellular ceramide formation, leading to the stimulation of cell proliferation and the suppression of apoptosis. Inhibition of p38 MAP kinase by SB203580 significantly reduced the serum deprivation-induced apoptosis. Over-expression of p38 increased the cell apoptosis and reduced the anti-apoptotic effect of TGF-β1. Inhibition of ERK1/ERK2 by PD98059 completely inhibited the TGF-β1-stimulated proliferation and partially inhibited the anti-apoptotic effects of TGF-β1. Neither SB203580 nor PD98059 has obvious effect on TGF-β1-mediated inhibition of the increased ceramide generation. Serum deprivation-induced apoptosis in NIH3T3 cells can also be blocked by broad-spectrum caspase inhibitor. TGF-β1 treatment has an inhibitory effect on caspase activities. Our results indicate that ceramide, p38, and ERK1/ERK2 play critical but differential roles in cell proliferation and stress-induced apoptosis. TGF-β1 suppresses the serum deprivation-induced
apoptosis via its distinct effects on complex signaling events involving the activation of ERK1/ERK2 and the inhibition of p38 activation and increased ceramide generation.
Serum deprivation induces apoptosis in NIH3T3 cells, which is associated with increased intracellular ceramide generation and with the activation of p38 mitogen-activated protein (MAP) kinase. Treatment of cells with transforming growth factor-β1 (TGF-β1) activated the extracellular signal regulated kinase 1 and 2 (ERK1/ERK2), inhibited the serum deprivation-induced p38 activation and the increase in intracellular ceramide formation, leading to the stimulation of cell proliferation and the suppression of apoptosis. Inhibition of p38 MAP kinase by SB203580 significantly reduced the serum deprivation-induced apoptosis. Over-expression of p38 increased the cell apoptosis and reduced the anti-apoptotic effect of TGF-β1. Inhibition of ERK1/ERK2 by PD98059 completely inhibited the TGF-β1-stimulated proliferation and partially inhibited the anti-apoptotic effects of TGF-β1. Neither SB203580 nor PD98059 has obvious effect on TGF-β1-mediated inhibition of the increased ceramide generation. Serum deprivation-induced apoptosis in NIH3T3 cells can also be blocked by broad-spectrum caspase inhibitor. TGF-β1 treatment has an inhibitory effect on caspase activities. Our results indicate that ceramide, p38, and ERK1/ERK2 play critical but differential roles in cell proliferation and stress-induced apoptosis. TGF-β1 suppresses the serum deprivation-induced
apoptosis via its distinct effects on complex signaling events involving the activation of ERK1/ERK2 and the inhibition of p38 activation and increased ceramide generation.
引文
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35. TAB1-dependent autophosphorylation of p38alpha. Science. 295: 1291-1294.
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40. Ruvolo PP (2001) Ceramide regulates cellular homeostasis via diverse stress signaling pathways. Leukemia 15: 1153-1160
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42. Hannun YA, Luberto C, Argraves KM (2001) Enzymes of sphingolipid metabolism : from modular to integrative signaling. Biochemistry. 40: 4893 4903
43. Mathias S, Pena LA, Kolesnick RN (1998) Signal transduction of stress via ceramide. Biochem. J. 335:465-480
44. Grassme H, Schwarz H, Gulbins E (2001) Molecular mechanisms of ceramide-mediated CD95 clustering. Biochem. Biophys. Res. Commun. 284: 1016-1030
45. Schissel S et al. (1998) Secretory sphingomyelinase, a product of the acid sphingomyelinase gene, can hydrolyze atherogenic lipoproteins at neutral pH. Implications for atherosclerotic lesion development. J. Biol. Chem. 273, 2738-2746
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47. Liu B et al. (1998) Glutathione regulation of neutral sphingomyelinase in tumor necrosis factor-alpha-induced cell death. J. Biol. Chem. 273: 11313-11320
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50. Chen JJ, Sun Y, Nabel GJ. (1998) Regulation of the proinflammatory effects of Fas ligand (CD95L). Science. 282: 1714-1717.
51. Kawakami A, Eguchi K, Matsuoka N, Tsuboi M, Kawabe Y, Aoyagi T, Nagataki S. (1996) Inhibition of Fas antigen-mediated apoptosis of rheumatoid synovial cells in vitro by transforming growth factor beta 1. Arthritis Rheum. 39: 1267-1276.
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55. Chen JS, Chai MQ, Chen HH, Zhao S and Song JG (2000) Regulation of phospholipase D activity and ceramide production in daunorubicin-induced apoptosis in A-431 cells. Biochim. Biophys. Acta. 1488: 219-232
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2. Massagué J, Blain SW and Lo RS (2000) TGFbeta signaling in growth control, cancer, and heritable disorders. Cell. 103: 295-309
3. Hahm KB, Im YH, Lee C, Parks WT, Bang YJ, Green JE and Kim SJ (2000) Loss of TGF-beta signaling contributes to autoimmune pancreatitis. J. Clin. Invest. 105: 1057-1065
4. Gorelik L and Flavell RA (2000) Abrogation of TGFbeta signaling in T cells leads to spontaneous T cell differentiation and autoimmune disease. Immunity 12: 171-181
5. Yue J and Mulder KM (2001) Transforming growth factor-beta signal transduction in epithelial cells. Pharmacol. Ther. 91: 1-34
6. Benzakour O, Merzak A, Dooghe Y, Pironin M, Lawrence D and Vigier P (1992) Transforming growth factor beta stimulates mitogenically mouse NIH3T3 fibroblasts and those cells transformed by the EJ-H ras oncogene. Growth Factors 6: 265-275
7. Dkhissi F, Raynal S, Jullien P and Lawrence DA (1999) Growth stimulation of murine fibroblasts by TGF-beta1 depends on the expression of a functional p53 protein. Oncogene 18: 703-711
8. Sánchez A, Alvarez AM, Benito M and Fabregat I (1996) Apoptosis induced by transforming growth factor-beta in fetal hepatocyte primary cultures: involvement of reactive oxygen intermediates. J. Biol. Chem. 271: 7416-7422
9. Fukuda K, Kojiro M and Chiu JF (1993) Induction of apoptosis by transforming growth factor-(1 in the rat hepatoma cell line McA-Rh7777: a possible association with tissue transglutaminase expression. Hepatology 18: 945-953
10. Arsura M, FitzGerald MJ, Fausto N and Sonenshein GE (1997) Nuclear factor-kappaB/Rel blocks transforming growth factor beta1-induced apoptosis of murine hepatocyte cell lines. Cell Growth Differ. 8: 1049-1059
Teramoto T, Kiss A and Thorgeirsson SS (1998) Induction of p53 and Bax during TGF-beta 1 initiated apoptosis in rat liver epithelial cells. Biochem.
11. Biophys. Res. Commun. 251: 56-60
12. Chin BY, Petrache I, Choi AM and Choi ME (1999) Transforming growth factor beta1 rescues serum deprivation-induced apoptosis via the mitogen-activated protein kinase (MAPK) pathway in macrophages. J. Biol. Chem. 274: 11362-11368
13. Huang Y, Hutter D, Liu Y, Wang X, Sheikh MS, Chan AM and Holbrook NJ (2000) Transforming growth factor-beta 1 suppresses serum deprivation-induced death of A549 cells through differential effects on c-Jun and JNK activities. J. Biol. Chem. 275: 18234-18242
14. Sparks RL and Scott RE (1986) Transforming growth factor type beta is a specific inhibitor of 3T3 T mesenchymal stem cell differentiation. Exp. Cell Res. 165: 345-352
15. Torti FM, Torti SV, Larrick JW and Ringold GM (1989) Modulation of adipocyte differentiation by tumor necrosis factor and transforming growth factor beta. J. Cell Biol. 108: 1105-1113
16. Petruschke T, Rohrig K and Hauner H (1994) Transforming growth factor beta (TGF-beta) inhibits the differentiation of human adipocyte precursor cells in primary culture. Int. J. Obes. Relat. Metab. Disord. 18: 532-536
17. Rahimi N, Tremblay E, McAdam L, Roberts A and Elliott B (1998) Autocrine secretion of TGF-beta 1 and TGF-beta 2 by pre-adipocytes and adipocytes: a potent negative regulator of adipocyte differentiation and proliferation of mammary carcinoma cells. In Vitro Cell Dev. Biol. Anim. 34: 412-420
18. Derynck R, Akhurst RJ and Balmain A (2001) TGF-beta signaling in tumor suppression and cancer progression. Nat. Genet. 29: 117-129
19. Wieser R (2001) The transforming growth factor-beta signaling pathway in tumorigenesis. Curr. Opin. Oncol. 13: 70-77
20. Moustakas A, Pardali K, Gaal A, Heldin CH (2002) Mechanisms of TGF-beta signaling in regulation of cell growth and differentiation. Immunol Lett. 82: 85-91.
21. Massagué J (2000) How cells read TGF-( signals. Nat. Rev. Mol. Cell Biol. 1: 169-178
Choy L, Skillington J and Derynck R (2000) Roles of autocrine TGF-( receptor and Smad signaling in adipocyte differentiation. J. Cell Biol. 149:
22. 667-681
23. Lutz M, Knaus P (2002) Integration of the TGF-beta pathway into the cellular signalling network. Cell Signal. 14: 977-88.
24. Rotzer D, Roth M, Lutz M, Lindemann D, Sebald W, Knaus P (2001) Type III TGF-beta receptor-independent signalling of TGF-beta2 via TbetaRII-B, an alternatively spliced TGF-beta type II receptor. EMBO J. 20: 480-90.
25. Heldin CH, Miyazono K and ten Dijke P (1997) TGF-beta signaling from cell membrane to nucleus through SMAD proteins. Nature 390: 465-471
26. Pearson G, Robinson F, Beers Gibson T, Xu BE, Karandikar M, Berman K and Cobb MH (2001) Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. Endocr. Rev. 22: 153-183
27. Derynck R, Akhurst RJ and Balmain A (2001) TGF-beta signaling in tumor suppression and cancer progression. Nat. Genet. 29: 117-129
28. Moustakas A, Souchelnytskyi S, Heldin CH (2001) Smad regulation in TGF-beta signal transduction. J Cell Sci. 114(Pt 24): 4359-4369.
29. Mulder KM (2000) Role of Ras and Mapks in TGFbeta signaling. Cytokine Growth Factor Rev. 11: 23-35
30. Chang L and Karin M (2001) Mammalian MAP kinase signaling cascades. Nature 410: 37-40
31. Huwiler A, Pfeilschifter J (1994) Transforming growth factor beta 2 stimulates acute and chronic activation of the mitogen-activated protein kinase cascade in rat renal mesangial cells. FEBS Lett. 354: 255-258.
32. Hartsough MT, Mulder KM (1995) Transforming growth factor beta activation of p44mapk in proliferating cultures of epithelial cells. J Biol Chem. 270: 7117-7124.
33. Yamaguchi K, Shirakabe K, Shibuya H, Irie K, Oishi I, Ueno N, Taniguchi T, Nishida E, Matsumoto K (1995) Identification of a member of the MAPKKK family as a potential mediator of TGF-beta signal transduction. Science. 270: 2008-2011.
34. Shibuya H, Yamaguchi K, Shirakabe K, Tonegawa A, Gotoh Y, Ueno N, Irie K, Nishida E, Matsumoto K (1996) TAB1: an activator of the TAK1 MAPKKK in TGF-beta signal transduction. Science. 272: 1179-1182.
Ge B, Gram H, Di Padova F, Huang B, New L, Ulevitch RJ, Luo Y, Han J (2002) MAPKK-independent activation of p38alpha mediated by
35. TAB1-dependent autophosphorylation of p38alpha. Science. 295: 1291-1294.
36. Larisch S, Yi Y, Lotan R, et al. (2000) A novel mitochondrial septin-like protein, ARTS, mediates apoptosis dependent on its P-loop motif. Nat Cell Biol. 2: 915-921.
37. Okazaki T, Kondo T, Kitano T and Tashima M (1998) Diversity and complexity of ceramide signaling in apoptosis. Cell Signal. 10: 685-692
38. Liu G, Kleine L and Hebert RL (1999) Advances in the signal transduction of ceramide and related sphingolipids. Crit. Rev. Clin. Lab. Sci. 36: 511-573
39. Hannun YA and Luberto C (2000) Ceramide in the eukaryotic stress response. Trends Cell Biol. 10: 73-80
40. Ruvolo PP (2001) Ceramide regulates cellular homeostasis via diverse stress signaling pathways. Leukemia 15: 1153-1160
41. Kolesnick R (2003) The therapeutic potential of modulating the ceramide/sphingomyelin pathway. J Clin Invest. 110: 3-8.
42. Hannun YA, Luberto C, Argraves KM (2001) Enzymes of sphingolipid metabolism : from modular to integrative signaling. Biochemistry. 40: 4893 4903
43. Mathias S, Pena LA, Kolesnick RN (1998) Signal transduction of stress via ceramide. Biochem. J. 335:465-480
44. Grassme H, Schwarz H, Gulbins E (2001) Molecular mechanisms of ceramide-mediated CD95 clustering. Biochem. Biophys. Res. Commun. 284: 1016-1030
45. Schissel S et al. (1998) Secretory sphingomyelinase, a product of the acid sphingomyelinase gene, can hydrolyze atherogenic lipoproteins at neutral pH. Implications for atherosclerotic lesion development. J. Biol. Chem. 273, 2738-2746
46. Liu P and Anderson R (1995) Compartmentalized production of ceramide at the cell surface. J. Biol. Chem. 270: 27179-27185
47. Liu B et al. (1998) Glutathione regulation of neutral sphingomyelinase in tumor necrosis factor-alpha-induced cell death. J. Biol. Chem. 273: 11313-11320
Merrill AH Jr, van Echten G, Wang E, Sandhoff K. (1993) Fumonisin B1 inhibits sphingosine (sphinganine) N-acyltransferase and de novo
48. sphingolipid biosynthesis in cultured neurons in situ. J Biol Chem. 268: 27299-27306.
49. Cerwenka A, Kovar H, Majdic O, Holter W. (1996) Fas- and activation-induced apoptosis are reduced in human T cells preactivated in the presence of TGF-beta 1. J Immunol. 156: 459-464.
50. Chen JJ, Sun Y, Nabel GJ. (1998) Regulation of the proinflammatory effects of Fas ligand (CD95L). Science. 282: 1714-1717.
51. Kawakami A, Eguchi K, Matsuoka N, Tsuboi M, Kawabe Y, Aoyagi T, Nagataki S. (1996) Inhibition of Fas antigen-mediated apoptosis of rheumatoid synovial cells in vitro by transforming growth factor beta 1. Arthritis Rheum. 39: 1267-1276.
52. Saile B, Matthes N, El Armouche H, Neubauer K, Ramadori G. (2001) The bcl, NFkappaB and p53/p21WAF1 systems are involved in spontaneous apoptosis and in the anti-apoptotic effect of TGF-beta or TNF-alpha on activated hepatic stellate cells. Eur J Cell Biol. 80: 554-561.
53. Schlapbach R, Spanaus KS, Malipiero U, Lens S, Tasinato A, Tschopp J, Fontana A (2000) TGF-beta induces the expression of the FLICE-inhibitory protein and inhibits Fas-mediated apoptosis of microglia. Eur J Immunol. 30: 3680-3688.
54. Ushio-Fukai M, Griendling KK, Akers M, Lyons PR and Alexander RW (1998) Temporal dispersion of activation of phospholipase C-beta1 and -gamma isoforms by angiotensin II in vascular smooth muscle cells. Role of alphaq/11, alpha12, and beta gamma G protein subunits. J. Biol. Chem. 273: 19772-19777
55. Chen JS, Chai MQ, Chen HH, Zhao S and Song JG (2000) Regulation of phospholipase D activity and ceramide production in daunorubicin-induced apoptosis in A-431 cells. Biochim. Biophys. Acta. 1488: 219-232
56. Zhao S, Du XY, Chai MQ, Chen JS, Zhou YC and Song JG (2002) Secretory phospholipase A(2) induces apoptosis via a mechanism involving ceramide generation. Biochim. Biophys. Acta. 1581: 75-88
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