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MEKK1-induced apoptosis requires TRAIL death receptor activation and is inhibited by AKT/PKB through inhibition of MEKK1 cleavage

Oncogene volume 21, pages 6649–6656 (2002)Cite this article

Abstract

MEK kinase 1 (MEKK1) induces apoptosis through the activation of caspases. The mechanism for MEKK1-induced apoptosis involves caspase-mediated cleavage of MEKK1, releasing a pro-apoptotic 91 kDa kinase fragment that serves to further amplify caspase activation in a feedback loop. Both cleavage of MEKK1 and increased expression of death receptor 4 (DR4, TRAILR1) and death receptor 5 (DR5, TRAILR2) occur following exposure of cells to genotoxins. Overexpression of kinase inactive MEKK1 inhibits MEKK1-mediated apoptosis and effectively blocks death receptor upregulation following etoposide treatment. Herein, we investigate the role of death receptor activation and the ability of AKT/PKB (AKT) to inhibit cell death in MEKK1-induced apoptosis. We show that by preventing DR4 and DR5 activation through expression of decoy receptor 1 (DcR1) and dominant negative FADD, we inhibit MEKK1-induced apoptosis. Furthermore, expression of 91 kDa MEKK1 increased DR4 and FAS mRNA and protein levels. MEKK1-induced apoptosis is amplified by blocking PI-3 kinase activation and overexpression of AKT blocked both MEKK1-induced apoptosis and caspase activation. AKT overexpression also prevented the cleavage of endogenous MEKK1 by genotoxins. AKT did not, however, block MEKK1-induced JNK activation, showing that regulation of the JNK pathway by MEKK1 is independent of its role in regulation of apoptosis. Thus, MEKK1-induced apoptosis requires TRAIL death receptor activation and is blocked by AKT through inhibition of MEKK1 cleavage.

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References

  • Ashkenazi A, Dixit VM . 1999 Curr. Opin. Cell Biol. 11: 255–260

  • Asselin E, Mills GB, Tsang BK . 2001 Cancer Res. 61: 1862–1868

  • Blume-Jensen P, Hunter T . 2001 Nature 411: 355–365

  • Cardone MH, Salvesen GS, Widmann C, Johnson G, Frisch SM . 1997 Cell 90: 315–323

  • Datta SR, Brunet A, Greenberg ME . 1999 Genes Dev. 13: 2905–2927

  • Deak JC, Cross JV, Lewis M, Qian Y, Parrott LA, Distelhorst CW, Templeton DJ . 1998 Proc. Natl. Acad. Sci. USA 95: 5595–5600

  • Di Cristofano A, Kotsi P, Peng YF, Cordon-Cardo C, Elkon KB, Pandolfi PP . 1999 Science 285: 2122–2125

  • Faris M, Kokot N, Latinis K, Kasibhatla S, Green DR, Koretzky GA, Nel A . 1998a J. Immunol. 160: 134–144

  • Faris M, Latinis KM, Kempiak SJ, Koretzky GA, Nel A . 1998b Mol. Cell. Biol. 18: 5414–5424

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

  • Gebauer G, Mirakhur B, Nguyen Q, Shore SK, Simpkins H, Dhanasekaran N . 2000 Int. J. Oncol. 16: 321–325

  • Gibson S, Widmann C, Johnson GL . 1999 J. Biol. Chem. 274: 10916–10922

  • Gibson SB, Oyer R, Spalding AC, Anderson SM, Johnson GL . 2000 Mol. Cell. Biol. 20: 205–212

  • Golstein P . 1997 Curr. Biol. 7: R750–R753

  • Green DR . 2000 Cell 102: 1–4

  • Griffith TS, Lynch DH . 1998 Curr. Opin. Immunol. 10: 559–563

  • Gura T . 1997 Science 277: 768

  • Khwaja A . 1999 Nature 401: 33–34

  • Lange-Carter CA, Pleiman CM, Gardner AM, Blumer KJ, Johnson GL . 1993 Science 260: 315–319

  • Lee SH, Shin MS, Kim HS, Lee HK, Park WS, Kim SY, Lee JH, Han SY, Park JY, Oh RR, Kang CS, Kim KM, Jang JJ, Nam SW, Lee JY, Yoo NJ . 2001 Oncogene 20: 399–403

  • Lin H, Chen C, Chen BD . 2001 Biochem. J. 353: 299–306

  • Mullauer L, Gruber P, Sebinger D, Buch J, Wohlfart S, Chott A . 2001 Mutat. Res. 488: 211–231

  • Pan G, O'Rourke K, Chinnaiyan AM, Gentz R, Ebner R, Ni J, Dixit VM . 1997 Science 276: 111–113

  • Panka DJ, Mano T, Suhara T, Walsh K, Mier JW . 2001 J. Biol. Chem. 276: 6893–6896

  • Schlesinger TK, Fanger GR, Yujiri T, Johnson GL . 1998 Front Biosci. 3: D1181–D1186

  • Sheridan JP, Marsters SA, Pitti RM, Gurney A, Skubatch M, Baldwin D, Ramakrishnan L, Gray CL, Baker K, Wood WI, Goddard AD, Godowski P, Ashkenazi A . 1997 Science 277: 818–821

  • Shin MS, Kim HS, Lee SH, Park WS, Kim SY, Park JY, Lee JH, Lee SK, Lee SN, Jung SS, Han JY, Kim H, Lee JY, Yoo NJ . 2001 Cancer Res. 61: 4942–4946

  • Soh JW, Mao Y, Liu L, Thompson WJ, Pamukcu R, Weinstein IB . 2001 J. Biol. Chem. 276: 16406–16410

  • Straus SE, Jaffe ES, Puck JM, Dale JK, Elkon KB, Rosen-Wolff A, Peters AM, Sneller MC, Hallahan CW, Wang J, Fischer RE, Jackson CM, Lin AY, Baumler C, Siegert E, Marx A, Vaishnaw AK, Grodzicky T, Fleisher TA, Lenardo MJ . 2001 Blood 98: 194–200

  • Tran J, Rak J, Sheehan C, Saibil SD, LaCasse E, Korneluk RG, Kerbel RS . 1999 Biochem. Biophys. Res. Commun. 264: 781–788

  • Tschopp J, Irmler M, Thome M . 1998 Curr. Opin. Immunol. 10: 552–558

  • Widmann C, Gerwins P, Johnson NL, Jarpe MB, Johnson GL . 1998 Mol. Cell. Biol. 18: 2416–2429

  • Widmann C, Gibson S, Jarpe MB, Johnson GL . 1999 Physiol. Rev. 79: 143–180

  • Widmann C, Johnson NL, Gardner AM, Smith RJ, Johnson GL . 1997 Oncogene 15: 2439–2447

  • Woo M, Hakem R, Soengas MS, Duncan GS, Shahinian A, Kagi D, Hakem A, McCurrach M, Khoo W, Kaufman SA, Senaldi G, Howard T, Lowe SW, Mak TW . 1998 Genes Dev. 12: 806–819

  • Yujiri T, Sather S, Fanger GR, Johnson GL . 1998 Science 282: 1911–1914

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Acknowledgements

AH Bild was supported by a DOD predoctoral fellowship DAMD17-98-1-8297. SB Gibson was supported in part by Canadian Institutes of Health Research.

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Authors and Affiliations

  1. Department of Pharmacology, University of Colorado, 2400 East Ninth Street, Denver, 80262, Colorado, CO, USA

    Andrea H Bild, Timothy P Garrington & Gary L Johnson

  2. Molecular Oncology Program, H Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, 33612, Florida, FL, USA

    Mei Huang & Richard Jove

  3. Manitoba Institute of Cell Biology, University of Manitoba, 675 McDermot Avenue, Winnipeg, R3E 0V9, Manitoba, Canada

    Francisco J Mendoza, Erika M Gibson, Jacylyn Villanueva & Spencer B Gibson

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  1. Andrea H Bild
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  2. Francisco J Mendoza
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Correspondence to Erika M Gibson.

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Bild, A., Mendoza, F., Gibson, E. et al. MEKK1-induced apoptosis requires TRAIL death receptor activation and is inhibited by AKT/PKB through inhibition of MEKK1 cleavage. Oncogene 21, 6649–6656 (2002). https://doi.org/10.1038/sj.onc.1205819

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