Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

The tyrosine kinase Lck is required for CD95-independent caspase-8 activation and apoptosis in response to ionizing radiation

Abstract

Induction of apoptosis is a hallmark of cytostatic drug and radiation-induced cell death in human lymphocytes and lymphoma cells. However, the mechanisms leading to apoptosis are not well understood. We provide evidence that ionizing radiation induces a rapid activation of caspase-8 (FLICE) followed by apoptosis independently of CD95 ligand/receptor interaction. The radiation induced cleavage pattern of procaspase-8 into mature caspase-8 resembled that following CD95 crosslinking and resulted in cleavage of the proapoptotic substrate BID. Overexpression of dominant-negative caspase-8 interfered with radiation-induced apoptosis. Caspase-8 activation by ionizing radiation was not observed in cells genetically defective for the Src-like tyrosine kinase Lck. Cells lacking Lck also displayed a marked resistance towards apoptosis induction upon ionizing radiation. After retransfection of Lck, caspase-8 activation and the capability to undergo apoptosis in response to ionizing radiation was restored. We conclude that radiation activates caspase-8 via an Lck-controlled pathway independently of CD95 ligand expression. This is a novel signaling event required for radiation induced apoptosis in T lymphoma cells.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  • Aldridge DR, Arends MJ and Radford IR. . 1995 Br. J. Cancer 71: 571–577.

  • Bauer MK, Vogt M, Los M, Siegel J, Wesselborg S and Schulze-Osthoff K. . 1998 J. Biol. Chem. 14: 8048–8055.

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

  • Chinnaiyan AM, O'Rourke K, Tewari M and Dixit VM. . 1995 Cell 81: 505–512.

  • Chou JJ, Matsuo H, Duan H and Wagner G. . 1998 Cell 94: 171–180.

  • Couture C, Songyang Z, Jascur T, Williams S, Tailor P, Cantley LC and Mustelin T. . 1996 J. Biol. Chem. 271: 24880–24804.

  • Dewey WC, Ling CC and Meyn RE. . 1995 Int. J. Radiat. Oncol. Biol. Phys. 33: 781–796.

  • Eischen CM, Dick CJ and Leibson PJ. . 1994 J. Immunol. 153: 1947–1954.

  • Eischen CM, Kottke TJ, Martins LM, Basi GS, Tung JS, Earnshaw WC, Leibson PJ and Kaufmann SH. . 1997 Blood 90: 935–943.

  • Farschon DM, Couture C, Mustelin T and Newmeyer DD. . 1997 J. Cell. Biol. 137: 1117–11125.

  • Ferrari D, Stepczynska A, Los M, Wesselborg S and Schulze-Osthoff K. . 1998 J. Exp. Med. 188: 979–984.

  • 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.

  • Hirata H, Takahashi A, Kobayashi S, Yonehara S, Sawai H, Okazaki T, Yamamoto K and Sasada M. . 1998 J. Exp. Med. 187: 587–600.

  • Hu Y, Benedict MA, Wu D, Inohara N and Nunez G. . 1998 Proc. Natl. Acad. Sci, USA 95: 4386–4391.

  • 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.

  • Juo P, Kuo CJ, Yuan J and Blenis J. . 1998 Curr. Biol. 10: 1001–1008.

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

  • Latinis KM and Koretzky GA. . 1996 Blood 87: 871–875.

  • Latinis KM, Carr LL, Peterson EJ, Norian LA, Eliason SL and Koretzky GA. . 1997 J. Immunol. 158: 4602–4611.

  • Leverkus M, Yaar M and Gilchrest BA. . 1997 Exp. Cell. Res. 232: 255–262.

  • Li H, Zhu H, Xu CJ and Yuan J. . 1998 Cell 94: 491–501.

  • Los M, Herr I, Friesen C, Fulda S, Schulze-Osthoff K and Debatin KM. . 1997 Blood 90: 3118–3129.

  • Lowe SW, Schmitt EM, Smith SW, Osborne BA and Jacks T. . 1993 Nature 362: 847–849.

  • Luo X, Budihardjo I, Zou H, Slaughter C and Wang X. . 1998 Cell 94: 481–490.

  • Miyashita T and Reed JC. . 1995 Cell 80: 293–299.

  • 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.

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

  • Pastorino JG, Chen ST, Tafani M, Snyder JW and Farber JL. . 1998 J. Biol. Chem. 273: 7770–7775.

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

  • Rosse T, Olivier R, Monney L, Rager M, Conus S, Fellay I, Jansen B and Borner C. . 1998 Nature 391: 496–499.

  • Sakakura C, Sweeney EA, Shirahama T, Igarashi Y, Hakomori S, Nakatani H, Tsujimoto H, Imanishi T, Ohgaki M, Ohyama T, Yamazaki J, Hagiwara A, Yamaguchi T, Sawai K and Takahashi T. . 1996 Int. J. Cancer 67: 101–105.

  • Salvesen GS and Dixit VM. . 1997 Cell 91: 443–446.

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

  • Straus DB and Weiss A. . 1992 Cell 70: 585–593.

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

  • Thornberry NA and Lazebnik Y. . 1998 Science 281: 1312–1316.

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

  • Villunger A, Egle A, Kos M, Hartmann BL, Geley S, Koffler R and Greil R. . 1997 Cancer Res. 57: 3331–3334.

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

  • 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.

Download references

Acknowledgements

We highly acknowledge the expert technical help from H Faltin and G Turan and supply of reagents by Drs E Alnemri, V Dixit, A Weiss and J Yuan. The work presented here was supported by a grant from the fortuene project (311/333 University of Tuebingen) to C Belka, E Gulbins and W Budach.

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Belka, C., Marini, P., Lepple-Wienhues, A. et al. The tyrosine kinase Lck is required for CD95-independent caspase-8 activation and apoptosis in response to ionizing radiation. Oncogene 18, 4983–4992 (1999). https://doi.org/10.1038/sj.onc.1202878

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1202878

Keywords

This article is cited by

Search

Quick links