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The tyrosine kinase Lck is involved in regulation of mitochondrial apoptosis pathways

Oncogene volume 22, pages 176–185 (2003)Cite this article

Abstract

The induction of apoptosis requires the activation of a highly coordinated signaling network ultimately leading to the activation of caspases. In previous experiments we and others have shown that the tyrosine kinase Lck is required for adequate apoptosis induction in response to ionizing radiation, ceramide incubation and overexpression of the HIV-TAT protein. However, the position of Lck within given apoptotic signaling cascades remains unclear. We therefore aimed to define the role of Lck during radiation-induced apoptosis. Apoptosis induction in response to ionizing radiation, CD95 or TRAIL receptor stimulation was determined in Jurkat T-cells, the Lck-deficient Jurkat clone JCaM1.6- and Lck-retransfected JCaM1.6/Lck. No apoptosis, release of cytochrome c, breakdown of the mitochondrial potential were detectable during the first 48 h after irradiation of JCaM1.6 cells. In parallel, no activation of caspase-9, -8 and -3 was detectable. Since mitochondrial apoptosis pathways act within a feedback mechanism during death-receptor-mediated apoptosis, the influence of the Lck defect on CD95/Fas/Apo-1-L or TRAIL-induced apoptosis was also tested. Both stimuli induced apoptosis in Lck-deficient cells. However, the kinetics of apoptosis induction determined by caspase-8, -9 and -3 activation as well as ΔΨm breakdown was slowed. We conclude that the Lck deficiency influences early steps during radiation-induced mitochondrial alterations.

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References

  • Belka C and Budach W. (2002). Int. J. Radiat. Biol., 78, 643–658.

  • Belka C, Knippers P, Rudner J, Faltin H, Bamberg M and Budach W. (2000a). Anticancer Res., 20, 3243–3249.

  • Belka C, Marini P, Budach W, Schulze-Osthoff K, Lang F, Gulbins E and Bamberg M. (1998). Radiat. Res., 149, 588–595.

  • 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. (2000b). 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.

  • Burek C, Roth J, Koch HG, Harzer K, Los M and Schulze-Osthoff K. (2001). Oncogene, 20, 6493–6502.

  • Cheng EH, Wei MC, Weiler S, Flavell RA, Mak TW, Lindsten T and Korsmeyer SJ. (2001). Mol. Cell., 8, 705–711.

  • Couture C, Songyang Z, Jascur T, Williams S, Tailor P, Cantley LC and Mustelin T. (1996). J. Biol. Chem., 271, 24880–24884.

  • Dunkern TR, Fritz G and Kaina B. (2001). Oncogene, 20, 6026–6038.

  • 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.

  • Farschon DM, Couture C, Mustelin T and Newmeyer DD. (1997). J. Cell Biol., 137, 1117–1125.

  • Friesen C, Herr I, Krammer PH and Debatin KM. (1996). Nat. Med., 2, 574–577.

  • Gulbins E, Szabo I, Baltzer K and Lang F. (1997). Proc. Natl. Acad. Sci. USA, 94, 7661–7666.

  • Hakem R, Hakem A, Duncan GS, Henderson JT, Woo M, Soengas MS, Elia A, de la Pompa JL, Kagi D, Khoo W, Potter J, Yoshida R, Kaufman SA, Lowe SW, Penninger JM and Mak TW. (1998). Cell, 94, 339–352.

  • Han J, Das B, Wei W, Van Aelst L, Mosteller RD, Khosravi-Far R, Westwick JK, Der CJ and Broek D. (1997). Mol. Cell Biol., 17, 1346–1353.

  • Jayaraman T and Marks AR. (1997). Mol. Cell Biol., 17, 3005–3012.

  • Jimenez B, Arends M, Esteve P, Perona R, Sanchez R, Ramon y Cajal S, Wyllie A and Lacal JC. (1995). Oncogene, 10, 811–816.

  • Kabouridis PS, Magee AI and Ley SC. (1997). EMBO J., 16, 4983–4998.

  • Kuida K, Haydar TF, Kuan CY, Gu Y, Taya C, Karasuyama H, Su MS, Rakic P and Flavell RA. (1998). Cell, 94, 325–337.

  • 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.

  • Manna SK and Aggarwal BB. (2000). J. Immunol., 164, 5156–5166.

  • Manna SK, Sah NK and Aggarwal BB. (2000). J. Biol. Chem., 275, 13297–13306.

  • 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.

  • Newton K and Strasser A. (2000). J. Exp. Med., 191, 195–200.

  • Ostergaard HL, Lou O, Arendt CW and Berg NN. (1998). J. Biol. Chem., 273, 5692–5696.

  • Pena LA, Fuks Z and Kolesnick RN. (2000). Cancer Res., 60, 321–327.

  • Qin S, Minami Y, Kurosaki T and Yamamura H. (1997). J. Biol. Chem., 272, 17994–17999.

  • Rudner J, Belka C, Marini P, Wagner RJ, Faltin H, Lepple-Wienhues A, Bamberg M and Budach W. (2001a). Int. J. Radiat. Biol., 77, 1–11.

  • 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. (2001b). J. Cell Sci., 114, 4161–4172.

  • Samelson LE. (2002). Annu. Rev. Immunol., 20, 371–394.

  • Santana P, Pena LA, Haimovitz-Friedman A, Martin S, Green D, McLoughlin M, Cordon-Cardo C, Schuchman EH, Fuks Z and Kolesnick R. (1996). Cell, 86, 189–199.

  • Schlottmann KE, Gulbins E, Lau SM and Coggeshall KM. (1996). J. Leukoc. Biol., 60, 546–554.

  • Schraven B and Peter ME. (1995). FEBS Lett., 368, 491–494.

  • Soengas MS, Alarcon RM, Yoshida H, Giaccia AJ, Hakem R, Mak TW and Lowe SW. (1999). Science, 284, 156–159.

  • Stepczynska A, Lauber K, Engels IH, Janssen O, Kabelitz D, Wesselborg S and Schulze-Osthoff K. (2001). Oncogene, 20, 1193–1202.

  • Straus DB and Weiss A. (1992). Cell, 70, 585–593.

  • Susin SA, Lorenzo HK, Zamzami N, Marzo I, Snow BE, Brothers GM, Mangion J, Jacotot E, Costantini P, Loeffler M, Larochette N, Goodlett DR, Aebersold R, Siderovski DP, Penninger JM and Kroemer G. (1999). Nature, 397, 441–446.

  • Szabo I, Lepple-Wienhues A, Kaba KN, Zoratti M, Gulbins E and Lang F. (1998). Proc. Natl. Acad. Sci. USA, 95, 6169–6174.

  • Tomicic MT, Thust R and Kaina B. (2002). Oncogene, 21, 2141–2153.

  • Tuosto L, Marinari B and Piccolella E. (2002). J. Immunol., 168, 6106–6112.

  • Uckun FM, Waddick KG, Mahajan S, Jun X, Takata M, Bolen J and Kurosaki T. (1996). Science, 273, 1096–1100.

  • Varfolomeev EE, Schuchmann M, Luria V, Chiannilkulchai N, Beckmann JS, Mett IL, Rebrikov D, Brodianski VM, Kemper OC, Kollet O, Lapidot T, Softer D, Sobe T, Avraham KB, Goncharov T, Holtmann H, Lonai P and Wallach D. (1998). Immunity, 9, 267–276.

  • von Haefen C, Wieder T, Gillissen B, Starck L, Graupner V, Dorken B and Daniel PT. (2002). Oncogene, 21, 4009–4019.

  • von Willebrand M, Williams S, Saxena M, Gilman J, Tailor P, Jascur T, Amarante-Mendes GP, Green DR and Mustelin T. (1998). J. Biol. Chem., 273, 3994–4000.

  • Waddick KG, Chae HP, Tuel-Ahlgren L, Jarvis LJ, Dibirdik I, Myers DE and Uckun FM. (1993). Radiat. Res., 136, 313–319.

  • Wei MC, Zong WX, Cheng EH, Lindsten T, Panoutsakopoulou V, Ross AJ, Roth KA, MacGregor GR, Thompson CB and Korsmeyer SJ. (2001). Science, 292, 727–730.

  • Wieder T, Essmann F, Prokop A, Schmelz K, Schulze-Osthoff K, Beyaert R, Dorken B and Daniel PT. (2001). Blood, 97, 1378–1387.

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Acknowledgements

The authors gratefully acknowledge the technical assistance of H Faltin. This work was supported by a grant of the Federal Ministry of Education and Research (Fö. 01KS9602) and the Interdisciplinary Center of Clinical research (IZKF) Tübingen to CB and by the Deutsche Krebshilfe/Mildred Scheel Stiftung (10-1825-Be2) to CB and VJ.

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  1. Claus Belka and Charlotte Gruber: These two authors share first authorship

Authors and Affiliations

  1. Department of Radiation Oncology, University of Tübingen, Hoppe Seyler Str. 3, Tübingen, D-72076, Germany

    Claus Belka, Charlotte Gruber, Verena Jendrossek & Wilfried Budach

  2. Department of Internal Medicine I, University of Tübingen, Otfried Müller Str. 10, Tübingen, D-72076, Germany

    Sebastian Wesselborg

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Correspondence to Claus Belka.

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Belka, C., Gruber, C., Jendrossek, V. et al. The tyrosine kinase Lck is involved in regulation of mitochondrial apoptosis pathways. Oncogene 22, 176–185 (2003). https://doi.org/10.1038/sj.onc.1206103

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