Abstract
Death receptor-induced apoptosis is paradigmatically mediated via the recruitment of FADD adapter molecule to the ligand/receptor complex and subsequent activation of caspase-8. However, several observations provided evidence that components of the mitochondrial apoptosis pathway are involved in death receptor-mediated apoptosis. In this regard, caspase-8-mediated activation of Bid induces the release of cytochrome c from the mitochondria, which, in turn, triggers the formation of the apoptosome protein complex, resulting in the activation of caspase-9. Whereas Bax or Bak were shown to be required for the proapoptotic effect of Bid, Bcl-2 was described to interfere with its action. Up to now, contradictory results regarding the role of Bcl-2 in TRAIL-induced apoptosis have been published. In order to study the influence of Bcl-2 on TRAIL-induced cell death more detailed, we utilized a tetracycline-regulated Bcl-2 expression system in Jurkat T cells. After having analysed the dose response for TRAIL-induced activation of caspase-8, -9, -3, breakdown of the mitochondrial membrane potential, and changes in the apoptotic morphology in cells expressing different Bcl-2 levels, we conclude that overexpression of Bcl-2 mediates a partial resistance towards lower doses of TRAIL that can be overcome when higher doses of TRAIL are applied. Thus, the requirement of the mitochondrial pathway for death receptor-induced apoptosis in type II cells should be reconsidered, since the protective effect of Bcl-2 is limited to lower TRAIL doses or early observation time points.
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References
Ashkenazi A, Pai RC, Fong S, Leung S, Lawrence DA, Marsters SA, Blackie C, Chang L, McMurtrey AE, Hebert A, DeForge L, Koumenis IL, Lewis D, Harris L, Bussiere J, Koeppen H, Shahrokh Z and Schwall RH . (1999). J. Clin. Invest., 104, 155–162.
Belka C, Betsch A, Marini P, Jendrossek V, Bamberg M and Budach W . (2003a). Strahlenther. Onkol., 179, 141–151.
Belka C and Budach W . (2002). Int. J. Radiat. Biol., 78, 643–658.
Belka C, Gruber C, Jendrossek V, Wesselborg S and Budach W . (2003b). Oncogene, 22, 176–185.
Belka C, Jendrossek V, Pruschy M, Vink S, Verheij M and Budach W . (2004). Int. J. Radiat. Oncol. Biol. Phys., 58, 542–554.
Belka C, Marini P, Lepple-Wienhues A, Budach W, Jekle A, Los M, Lang F, Schulze-Osthoff K, Gulbins E and Bamberg M . (1999). Oncogene, 18, 4983–4992.
Belka C, Rudner J, Wesselborg S, Stepczynska A, Marini P, Lepple-Wienhues A, Faltin H, Bamberg M, Budach W and Schulze-Osthoff K . (2000). Oncogene, 19, 1181–1190.
Belka C, Schmid B, Marini P, Durand E, Rudner J, Faltin H, Bamberg M, Schulze-Osthoff K and Budach W . (2001). Oncogene, 20, 2190–2196.
Cheng EH, Wei MC, Weiler S, Flavell RA, Mak TW, Lindsten T and Korsmeyer SJ . (2001). Mol. Cell, 8, 705–711.
Chinnaiyan AM, O'Rourke K, Tewari M and Dixit VM . (1995). Cell, 81, 505–512.
de Almodovar CR, Ruiz-Ruiz C, Munoz-Pinedo C, Robledo G and Lopez-Rivas A . (2001). Oncogene, 20, 7128–7133.
Degli Esposti M, Ferry G, Masdehors P, Boutin JA, Hickman JA and Dive C . (2003). J. Biol. Chem., 278, 15749–15757 (Epub 2003 February 21).
Dhein J, Walczak H, Baumler C, Debatin KM and Krammer PH . (1995). Nature, 373, 438–441.
Engels IH, Stepczynska A, Stroh C, Lauber K, Berg C, Schwenzer R, Wajant H, Janicke RU, Porter AG, Belka C, Gregor M, Schulze-Osthoff K and Wesselborg S . (2000). Oncogene, 19, 4563–4573.
Erickson SL, de Sauvage FJ, Kikly K, Carver-Moore K, Pitts-Meek S, Gillett N, Sheehan KC, Schreiber RD, Goeddel DV and Moore MW . (1994). Nature, 372, 560–563.
Fischer U, Janicke RU and Schulze-Osthoff K . (2003). Cell Death Differ., 10, 76–100.
Fulda S, Meyer E and Debatin KM . (2002). Oncogene, 21, 2283–2294.
Gazitt Y . (1999). Leukemia, 13, 1817–1824.
Guner D, Belka C and Daniel PT . (2003). Curr. Med. Chem. Anti-Cancer Agents, 3, 319–326.
Held J and Schulze-Osthoff K . (2001). Drug Resist. Updates, 4, 243–252.
Hinz S, Trauzold A, Boenicke L, Sandberg C, Beckmann S, Bayer E, Walczak H, Kalthoff H and Ungefroren H . (2000). Oncogene, 19, 5477–5486.
Holler N, Tardivel A, Kovacsovics-Bankowski M, Hertig S, Gaide O, Martinon F, Tinel A, Deperthes D, Calderara S, Schulthess T, Engel J, Schneider P and Tschopp J . (2003). Mol. Cell. Biol., 23, 1428–1440.
Huang DC, Hahne M, Schroeter M, Frei K, Fontana A, Villunger A, Newton K, Tschopp J and Strasser A . (1999). Proc. Natl. Acad. Sci. USA, 96, 14871–14876.
Huang DC, Tschopp J and Strasser A . (2000). Cell Death Differ., 7, 754–755.
Jendrossek V, Handrick R and Belka C . (2003a). FASEB J., 17, 1547–1549 (Epub 2003 June 17).
Jendrossek V, Muller I, Eibl H and Belka C . (2003b). Oncogene, 22, 2621–2631.
Jo M, Kim TH, Seol DW, Esplen JE, Dorko K, Billiar TR and Strom SC . (2000). Nat. Med., 6, 564–567.
Johnson TR, Stone K, Nikrad M, Yeh T, Zong WX, Thompson CB, Nesterov A and Kraft AS . (2003). Oncogene, 22, 4953–4963.
Keogh SA, Walczak H, Bouchier-Hayes L and Martin SJ . (2000). FEBS Lett., 471, 93–98.
Kim EH, Kim SU, Shin DY and Choi KS . (2004). Oncogene, 23, 446–456.
Kim IK, Jung YK, Noh DY, Song YS, Choi CH, Oh BH and Masuda ES . (2003). Br. J. Cancer, 88, 910–917.
Kischkel FC, Lawrence DA, Tinel A, LeBlanc H, Virmani A, Schow P, Gazdar A, Blenis J, Arnott D and Ashkenazi A . (2001). J. Biol. Chem., 276, 46639–46646.
Kluck RM, Bossy-Wetzel E, Green DR and Newmeyer DD . (1997). Science, 275, 1132–1136.
Krammer PH, Dhein J, Walczak H, Behrmann I, Mariani S, Matiba B, Fath M, Daniel PT, Knipping E and Westendorp MO . (1994). Immunol. Rev., 142, 175–191.
Lacour S, Micheau O, Hammann A, Drouineaud V, Tschopp J, Solary E and Dimanche-Boitrel MT . (2003). Oncogene, 22, 1807–1816.
Lawrence D, Shahrokh Z, Marsters S, Achilles K, Shih D, Mounho B, Hillan K, Totpal K, DeForge L, Schow P, Hooley J, Sherwood S, Pai R, Leung S, Khan L, Gliniak B, Bussiere J, Smith CA, Strom SS, Kelley S, Fox JA, Thomas D and Ashkenazi A . (2001). Nat. Med., 7, 383–385.
Li H, Zhu H, Xu CJ and Yuan J . (1998). Cell, 94, 491–501.
Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES and Wang X . (1997). Cell, 91, 479–489.
Luo X, Budihardjo I, Zou H, Slaughter C and Wang X . (1998). Cell, 94, 481–490.
Marini P, Jendrossek V, Durand E, Gruber C, Budach W and Belka C . (2003). Radiother. Oncol., 68, 189–198.
Medema JP, Scaffidi C, Krammer PH and Peter ME . (1998). J. Biol. Chem., 273, 3388–3393.
Mills KR, Reginato M, Debnath J, Queenan B and Brugge JS . (2004). Proc. Natl. Acad. Sci. USA, 101, 3438–3443 (Epub 2004 March 1).
Muzio M, Chinnaiyan AM, Kischkel FC, O'Rourke K, Shevchenko A, Ni J, Scaffidi C, Bretz JD, Zhang M, Gentz R, Mann M, Krammer PH, Peter ME and Dixit VM . (1996). Cell, 85, 817–827.
Muzio M, Stockwell BR, Stennicke HR, Salvesen GS and Dixit VM . (1998). J. Biol. Chem., 273, 2926–2930.
Nagata S . (2000). Nat. Med., 6, 502–503.
Pitti RM, Marsters SA, Ruppert S, Donahue CJ, Moore A and Ashkenazi A . (1996). J. Biol. Chem., 271, 12687–12690.
Prokop A, Wrasidlo W, Lode H, Herold R, Lang F, Henze G, Dorken B, Wieder T and Daniel PT . (2003). Oncogene, 22, 9107–9120.
Rodriguez I, Matsuura K, Khatib K, Reed JC, Nagata S and Vassalli P . (1996). J. Exp. Med., 183, 1031–1036.
Rothe J, Lesslauer W, Lotscher H, Lang Y, Koebel P, Kontgen F, Althage A, Zinkernagel R, Steinmetz M and Bluethmann H . (1993). Nature, 364, 798–802.
Rudner J, Jendrossek V and Belka C . (2002). Apoptosis, 7, 441–447.
Rudner J, Lepple-Wienhues A, Budach W, Berschauer J, Friedrich B, Wesselborg S, Schulze-Osthoff K and Belka C . (2001). J. Cell. Sci., 114, 4161–4172.
Ruffolo SC and Shore GC . (2003). J. Biol. Chem., 29, 29.
Ruiz de Almodovar C, Ruiz-Ruiz C, Munoz-Pinedo C, Robledo G and Lopez-Rivas A . (2001). Oncogene, 20, 7128–7133.
Saleh A, Srinivasula SM, Acharya S, Fishel R and Alnemri ES . (1999). J. Biol. Chem., 274, 17941–17945.
Salvesen GS and Dixit VM . (1997). Cell, 91, 443–446.
Scaffidi C, Fulda S, Srinivasan A, Friesen C, Li F, Tomaselli KJ, Debatin KM, Krammer PH and Peter ME . (1998). EMBO J., 17, 1675–1687.
Scaffidi C, Schmitz I, Zha J, Korsmeyer SJ, Krammer PH and Peter ME . (1999). J. Biol. Chem., 274, 22532–22538.
Schmitz I, Walczak H, Krammer PH and Peter ME . (1999). Cell Death Differ., 6, 821–822.
Sheridan JP, Marsters SA, Pitti RM, Gurney A, Skubatch M, Baldwin D, Ramakrishnan L, Gray CL, Baker K, Wood WI, Goddard AD, Godowski P and Ashkenazi A . (1997). Science, 277, 818–821.
Stennicke HR, Jurgensmeier JM, Shin H, Deveraux Q, Wolf BB, Yang X, Zhou Q, Ellerby HM, Ellerby LM, Bredesen D, Green DR, Reed JC, Froelich CJ and Salvesen GS . (1998). J. Biol. Chem., 273, 27084–27090.
Strasser A, Harris AW, Huang DC, Krammer PH and Cory S . (1995). EMBO J., 14, 6136–6147.
Suliman A, Lam A, Datta R and Srivastava RK . (2001). Oncogene, 20, 2122–2133.
Sun SY, Yue P, Zhou JY, Wang Y, Choi Kim HR, Lotan R and Wu GS . (2001). Biochem. Biophys. Res. Commun., 280, 788–797.
Sun XM, Bratton SB, Butterworth M, MacFarlane M and Cohen GM . (2002a). J. Biol. Chem., 18, 18.
Sun XM, Bratton SB, Butterworth M, MacFarlane M and Cohen GM . (2002b). J. Biol. Chem., 277, 11345–11351.
Takeda K, Hayakawa Y, Smyth MJ, Kayagaki N, Yamaguchi N, Kakuta S, Iwakura Y, Yagita H and Okumura K . (2001). Nat. Med., 7, 94–100.
Tecchio C, Huber V, Scapini P, Calzetti F, Margotto D, Todeschini G, Pilla L, Martinelli G, Pizzolo G, Rivoltini L and Cassatella MA . (2004). Blood, 15, 15.
Velthuis JH, Rouschop KM, De Bont HJ, Mulder GJ and Nagelkerke JF . (2002). J. Biol. Chem., 277, 24631–24637.
von Haefen C, Wieder T, Gillissen B, Starck L, Graupner V, Dorken B and Daniel PT . (2002). Oncogene, 21, 4009–4019.
Wajant H, Pfizenmaier K and Scheurich P . (2002). Apoptosis, 7, 449–459.
Walczak H, Bouchon A, Stahl H and Krammer PH . (2000). Cancer Res., 60, 3051–3057.
Walczak H, Miller RE, Ariail K, Gliniak B, Griffith TS, Kubin M, Chin W, Jones J, Woodward A, Le T, Smith C, Smolak P, Goodwin RG, Rauch CT, Schuh JC and Lynch DH . (1999). Nat. Med., 5, 157–163.
Wang K, Yin XM, Chao DT, Milliman CL and Korsmeyer SJ . (1996). Genes Dev., 10, 2859–2869.
Weinmann M, Marini P, Jendrossek V, Betsch A, Goecke B, Budach W and Belka C . (2004). Int. J. Radiat. Oncol. Biol. Phys., 58, 386–396.
Weller M, Malipiero U, Aguzzi A, Reed JC and Fontana A . (1995). J. Clin. Invest., 95, 2633–2643.
Yi X, Yin XM and Dong Z . (2003). J. Biol. Chem., 278, 16992–16999.
Yin XM, Wang K, Gross A, Zhao Y, Zinkel S, Klocke B, Roth KA and Korsmeyer SJ . (1999). Nature, 400, 886–891.
Zhang XD, Borrow JM, Zhang XY, Nguyen T and Hersey P . (2003). Oncogene, 22, 2869–2881.
Zhang XD, Zhang XY, Gray CP, Nguyen T and Hersey P . (2001). Cancer Res., 61, 7339–7348.
Acknowledgements
This study was supported by grants from the Interdisciplinary Centre for Clinical Research (IZKF IIIB3) to CB and from Deutsche Krebshilfe to CB and VJ 10-1764Be1, CB 10-1825Be2, and CB10-1970Be3.
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Rudner, J., Jendrossek, V., Lauber, K. et al. Type I and type II reactions in TRAIL-induced apoptosis – results from dose–response studies. Oncogene 24, 130–140 (2005). https://doi.org/10.1038/sj.onc.1208191
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DOI: https://doi.org/10.1038/sj.onc.1208191
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