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:

Requirement of protein kinase (Krs/MST) activation for MT-21-induced apoptosis

Oncogene volume 18, pages 5211–5220 (1999)Cite this article

Abstract

Fas is a well characterized apoptosis-inducing factor. One of our synthetic compounds, MT-21, induced apoptosis in human leukemia HL-60 cells similar to Fas. MT-21 activated caspase-3, an important cysteine aspartic protease for apoptosis induction. MT-21 also activated c-Jun-NH2-terminal kinase (JNK), a member of mitogen activated protein kinase (MAPK) superfamily that is involved in the regulation of cell growth, differentiation and cell death. Moreover, MT-21 treatment resulted in the activation of a 36 kDa kinase which uses myelin basic protein (MBP) as a substrate. However, MAPK and p38 were not activated by treatment with MT-21. The 36 kDa MBP kinase was shown to be a proteolytic product derived from the Krs protein with a molecular weight of 60 kDa. The Krs protein is a Ser/Thr protein kinase whose activity is enhanced by digestion of its C-terminal regulatory domain by caspase-3. When a kinase-inactive mutant form of Krs protein was overexpressed in HL-60 cells, JNK activation and apoptosis induction by MT-21 were suppressed. Furthermore, overexpression of dominant negative c-Jun also suppressed apoptosis induction by MT-21. These findings indicate that MT-21 induces apoptosis by the activation of JNK via the Krs protein, which is activated by caspase cleavage.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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
Figure 8
Figure 9

Similar content being viewed by others

References

  • Boldin MP, Goncharov TM, Goltsev YV and Wallach D. . 1996 Cell 85: 803–815.

  • Cahill MA, Peter ME, Kischkel FC, Chinnaiyan AM, Dixit VM, Krammer PH and Nordheim A. . 1996 Oncogene 13: 2087–2096.

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

  • Casciola Rosen LA, Anhalt GJ and Rosen A. . 1995 J. Exp. Med. 182: 1625–1634.

  • Chinnaiyan AM, Orth K, O'Rourke K, Duan H, Poirier GG and Dixit VM. . 1996 J. Biol. Chem. 271: 4573–4576.

  • Creasy CL, Ambrose DM and Chernoff J. . 1996 J. Biol. Chem. 21049–21053.

  • Creasy CL and Chernoff J. . 1995 J. Biol. Chem. 270: 21695–21700.

  • Crouch DH, Fincham VJ and Frame MC. . 1996 Oncogene 12: 2689–2696.

  • Cryns VL, Byun Y, Rana A, Mellor H, Lustig KD, Ghanem L, Parker PJ, Kischner MW and Yuan JY. . 1997 J. Biol. Chem. 272: 29449–29453.

  • Darmon AJ, Ley TJ, Nicholson DW and Bleackley RC. . 1996 J. Biol. Chem. 271: 21709–21712.

  • Datta AK. . 1995 Nucleic Acids Res. 23: 4530–4531.

  • Dubrez L, Savoy I, Hamman A and Solary E. . 1996 EMBO J. 15: 5504–5512.

  • Emoto Y, Manome Y, Meinhardt G, Kisaki H, Kharbanda S, Robertson M, Ghayur H, Wong WW, Kamen R, Weichselbaum R and Kufe D. . 1995 EMBO J. 14: 6148–6156.

  • Erhardt P and Cooper GM. . 1996 J. Biol. Chem. 271: 17601–17604.

  • Graves JD, Draves KE, Craxton A, Saklatvala J, Krebs EG and Clark EA. . 1996 Proc. Natl. Acad. Sci. USA 93: 13814–13818.

  • Graves JD, Gotoh Y, Draves KE, Ambrose D, Han DKM, Wright M, Chernoff J, Clark EA and Krebs EG. . 1998 EMBO J. 17: 2224–2234.

  • Hasegawa J, Kamada S, Kamiike W, Shimizu S, Imazu T, Matsuda H and Tsujimoto Y. . 1996 Cancer Res. 56: 1713–1718.

  • Hockenbery DM, Oltvai ZN, Yin X, Milliman CL and Korsmeyer SJ. . 1993 Cell 75: 241–251.

  • Jacobson MD. . 1996 Trends Biochem. Sci. 19: 83–86.

  • Jacobson MD, Weil M and Raff MC. . 1996 J. Cell Biol. 133: 1041–1051.

  • Juo P, Kuo CJ, Reynolds SE, Konz RF, Raingeaud RF, Daviv RJ, Biemann HP and Blenis J. . 1997 Mol. Cell Biol. 17: 24–35.

  • Kakeya H, Onose R and Osada H. . 1998 Cancer Res. 58: 4888–4894.

  • Kakeya H, Onozawa C, Sato M, Arai K and Osada H. . 1997 J. Med. Chem. 40: 391–394.

  • Kakeya H, Takahashi I, Okada G, Isono K and Osada H. . 1995 J. Antibiot. 48: 733–735.

  • Laemmli UK. . 1970 Nature 227: 680–685.

  • Lazebnik YA, Kaufmann SH, Desnoyers S, Poirier GG and Earnshaw WC. . 1994 Nature 371: 346–347.

  • Lee KK, Murakawa M, Nishida E, Tsubuki S, Kawashima K, Sakamaki K and Yonehara S. . 1998 Oncogene 16: 3029–3037.

  • Longthorne VL and Williams GT. . 1997 EMBO J. 16: 3805–3812.

  • Lu ML, Sato M, Cao B and Richie JP. . 1996 Proc. Natl. Acad. Sci. USA 93: 8977–8982.

  • Mashima T, Naito M, Noguchi K, Miller DK, Nicholson DW and Tsuruo T. . 1997 Oncogene 14: 1007–1012.

  • Muzio M, Chinnaiyan AM, Kischkel FC, O'Rourke K, Shevchenko A, Scaffidi C, Bretz JD, Zhang M, Ni J, Gentz R, Mann M, Krammer PH, Peter ME and Dixit VM. . 1996 Cell 85: 817–827.

  • Na S, Chuang TH, Cunningham A, Turi TG, Hanke JH, Bokoch GM and Danley DE. . 1996 J. Biol. Chem. 271: 11209–11213.

  • Nicholson WD, Ali A, Thornberry NA, Vaillancourt JP, Ding CK, Gallant M, Gareau Y, Griffin PR, Labelle M, Lazebnik YA, Munday NA, Raju SM, Smulson ME, Yamin TT, Yu VL and Miller DK. . 1995 Nature 376: 37–43.

  • Orth K, Chinnaiyan AM, Garg M, Froelich CJ and Dixit VM. . 1996 J. Biol. Chem. 271: 16443–16446.

  • Royall JA and Ischiropoulos H. . 1993 Arch. Biochem. Biophys. 302: 348–355.

  • Rudel T and Bokoch GM. . 1997 Science 276: 1571–1574.

  • Sakahira H, Enari M and Nagata S. . 1998 Nature 391: 96–99.

  • Schlegel J, Peter I, Orrenius S, Miller DK, Thornberry NA, Yamin TT and Nicholson DW. . 1996 J. Biol. Chem. 271: 1841–1844.

  • Simizu S, Imoto M, Masuda N, Takada M and Umezawa K. . 1996 Cancer Res. 56: 4978–4982.

  • Takahashi A, Musy PY, Martins LM, Poirier GG, Moyer RW and Earnshaw WC. . 1996 J. Biol. Chem. 271: 32487–32490.

  • Taylor LK, Wang H-CR and Erikson RL. . 1996 Proc. Natl. Acad. Sci. USA 93: 10099–10104.

  • Thornberry NA and Molineaux SM. . 1995 Protein Sci. 4: 3–12.

  • Wang X, Zelenski NG, Yang J, Sakai J, Brown MS and Goldstein JL. . 1996 EMBO J. 15: 1012–1020.

  • Watabe M, Ito K, Masuda Y, Nakajo S and Nakaya K. . 1998 Oncogene 16: 779–787.

  • Watabe M, Masuda Y, Nakajo S, Yoshida T, Kuroiwa Y and Nakaya K. . 1996 J. Biol. Chem. 271: 14067–14073.

  • Wilson DJ, Fortner KA, Lynch DH, Mattingly RR, Macara IG, Posada JA and Budd RC. . 1996 Eur. J. Immunol. 26: 989–994.

  • Xia Z, Dickens M, Raingeaud J, Davis RJ and Greenberg ME. . 1995 Science 270: 1326–1331.

Download references

Acknowledgements

MT-21 and U937 cells transfected with dominant negative c-Jun are a generous gift from Taisho Pharmaceutical Co. Ltd (Tokyo, Japan) and Dr K Nakaya (Showa University), respectively. Helpful discussion with EC Griffith gratefully acknowledged. This work was supported in part by a Grant for Multibioprobes (RIKEN), a Grant from the Ministry of Education, Science, Sports, and Culture, Japan, and a Special Postdoctoral Researchers Program to M Watabe.

Author information

Authors and Affiliations

  1. Laboratory of Antibiotics, The Institute of Physical and Chemical Research (RIKEN), 2-1 Hirosawa, Wako, 351-0198, Saitama, Japan

    Masahiko Watabe, Hideaki Kakeya & Hiroyuki Osada

Authors
  1. Masahiko Watabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hideaki Kakeya
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hiroyuki Osada
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Watabe, M., Kakeya, H. & Osada, H. Requirement of protein kinase (Krs/MST) activation for MT-21-induced apoptosis. Oncogene 18, 5211–5220 (1999). https://doi.org/10.1038/sj.onc.1202901

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1202901

Keywords

This article is cited by

Search

Advanced search

Quick links