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:

Double-stranded RNA-dependent protein kinase, PKR, down-regulates CDC2/cyclin B1 and induces apoptosis in non-transformed but not in v-mos transformed cells

Oncogene volume 20, pages 8045–8056 (2001)Cite this article

Abstract

The interferon (IFN)-induced, double stranded RNA (dsRNA)-activated serine/threonine kinase, PKR, is a potent negative regulator of cell growth when overexpressed in yeast or mammalian cells. Paradoxically, while it can function as a tumor suppressor and inducer of apoptosis, it is overexpressed in a variety of human cancers. To resolve this enigma, we established cell-lines that overexpress PKR in non-transformed and in v-mos transformed CHO cells. Overexpression of PKR suppressed the proliferation of CHO cells by inducing a transient G0/G1 arrest, followed by a delayed G2/M arrest, which attenuated cell cycle progression. These effects were accompanied by early induction of p21/WAF-1 and delayed downregulation of CDC2 and cyclin B1. Induction of proapoptotic activity of the ectopic PKR paralleled the onset of G2/M arrest in CHO cells. However, while transiently inducing p21/WAF-1, PKR did not impose G2/M arrest or apoptosis in v-mos-transformed cells, nor was CDC2 or cyclin B1 down-regulated in those cells. These findings link the proapoptotic activity of PKR to the arrest of cell cycle at the G2/M phase. Consequently, the apoptotic activity of PKR could be counter-acted by an oncogene-like v-mos that overrides the G2/M arrest induced by PKR.

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
Figure 10
Figure 11

Similar content being viewed by others

References

  • Afshari CA, Rhodes N, Paules RS, Mudryj M . 1997 Oncogene 14: 3029–3038

  • Barber GN, Jagus R, Meurs EF, Hovanessian AG, Katze MG . 1995 J. Biol. Chem. 270: 17423–17428

  • Barber GN, Tomita J, Garfinkel MS, Meurs E, Hovanessian A, Katze MG . 1992 Virology 191: 670–679

  • Blair DG, Oskarsson M, Wood TG, McClements WL, Fischinger PJ, Vande Woude GG . 1981 Science 212: 941–943

  • Canaani E, Dreazen O, Klar A, Rechavi G, Ram D, Cohen JB, Givol D . 1983 Proc. Natl. Acad. Sci. USA 80: 7118–7122

  • Chen FW, Ioannou YA . 1999 Int. Rev. Immunol. 18: 429–448

  • Chong KL, Feng L, Schappert K, Meurs E, Donahue TF, Friesen JD, Hovanessian AG, Williams BR . 1992 EMBO J. 11: 1553–1562

  • Craddock BL, Price NT, Proud CG . 1995 Biochem. J. 309: 1009–1014

  • Cuddihy AR, Li S, Tam NW, Wong AH, Taya Y, Abraham N, Bell JC, Koromilas AE . 1999a Mol. Cell. Biol. 19: 2475–2484

  • Cuddihy AR, Wong AH, Tam NW, Li S, Koromilas AE . 1999b Oncogene 18: 2690–2702

  • de Moor CH, Richter JD . 1997 Mol. Cell. Biol. 17: 6419–6426

  • Farrell PJ, Balkow K, Hunt T, Jackson RJ, Trachsel H . 1977 Cell 11: 187–200

  • Gil J, Alcami J, Esteban M . 1999 Mol. Cell. Biol. 19: 4653–4663

  • Gil J, Esteban M . 2000 Apoptosis 5: 107–114

  • Gil J, Esteban M, Roth D . 2000 Biochemistry 39: 7521–7530

  • Haines GK, Becker S, Ghadge G, Kies M, Pelzer H, Radosevich JA . 1993a Arch. Otolaryngol. Head Neck Surg. 119: 1142–1147

  • Haines GK, Cajulis R, Hayden R, Duda R, Talamonti M, Radosevich JA . 1996 Tumor Biol. 17: 5–12

  • Haines GK, Ghadge G, Thimmappaya B, Radosevich JA . 1992 Mol. Pathol. 62: 151–158

  • Haines GK, Ghadge GD, Becker S, Kies M, Pelzer H, Thimmappaya B, Radosevich JA . 1993b Mol. Pathol. 63: 289–295

  • Haines GK, Panos RJ, Bak PM, Brown T, Zielinski M, Leyland J, Radosevich JA . 1998 Tumour. Biol. 19: 52–59

  • Hannigan G, Williams BR . 1986 EMBO J. 5: 1607–1613

  • Henry GL, McCormack SJ, Thomis DC, Samuel CE . 1994 J. Biol. Regul. Homeost. Agents 8: 15–24

  • Hershey JW . 1991 Annu. Rev. Biochem. 60: 717–755

  • Hovanessian AG . 1993 Semin. Virol. 4: 237–245

  • Ito T, Yang M, May WS . 1999 J. Biol. Chem. 274: 15427–15432

  • Kerr IM, Brown RE, Hovanessian AG . 1977 Nature 268: 540–542

  • Kim SH, Forman AP, Mathews MB, Gunnery S . 2000 Oncogene 19: 3086–3094

  • Kishimoto T . 1999 Dev. Biol. 214: 1–8

  • Koromilas AE, Roy S, Barber GN, Katze MG, Sonenberg N . 1992 Science 257: 1685–1689

  • Kozak M . 1988 J. Cell Biol. 107: 1–7

  • Kronfeld-Kinar Y, Vilchik S, Hyman T, Leibkowicz F, Salzberg S . 1999 Cell Growth Differ. 10: 201–212

  • Kumar A, Haque J, Lacoste J, Hiscott J, Williams BR . 1994 Proc. Natl. Acad. Sci. USA 91: 6288–6292

  • Lee SB, Esteban M . 1994 Virology 199: 491–496

  • Li S, Koromilas AE . 2001 J. Biol. Chem. 276: 13881–13890

  • Li S, Nagai K, Koromilas AE . 2000 Eur. J. Biochem. 267: 1598–1606

  • Lohka MJ . 1989 J. Cell Sci. 92: 131–135

  • Lorca T . 1993 Pathol. Biol. (Paris) 41: 260–267

  • Lu J, O'Hara EB, Trieselmann BA, Romano PR, Dever TE . 1999 J. Biol. Chem. 274: 32198–32203

  • Maller JL . 1990 Biochemistry 29: 3157–3166

  • Maxwell SA, Arlinghaus RB . 1985 Virology 143: 321–333

  • Melville MW, Katze MG, Tan SL . 2000 Cell Mol. Life Sci. 57: 311–322

  • Meurs EF, Galabru J, Barber GN, Katze MG, Hovanessian AG . 1993 Proc. Natl. Acad. Sci. USA 90: 232–236

  • Meurs EF, Watanabe Y, Kadereit S, Barber BN, Katze MG, Chong K, Williams BR, Hovanessian AG . 1992 J. Virol. 66: 5804–5814

  • Mundschau LJ, Faller DV . 1992 J. Biol. Chem. 267: 23092–23098

  • Mundschau LJ, Faller DV . 1994 Biochimie 76: 792–800

  • Nebreda AR, Hunt T . 1993 EMBO J. 12: 1979–1986

  • No D, Yao TO, Evans RM . 1996 Proc. Natl. Acad. Sci. USA, 93: 3346–3351

  • Nurse P . 1990 Nature 344: 503–508

  • Pain VM . 1996 Eur. J. Biochem. 236: 747–771

  • Paules RS, Resnick J, Kosenally AB, Ernst MK, Donovan P, Vande Woude GF . 1992 Oncogene 7: 2489–2498

  • Posada J, Yew N, Ahn NG, Vande Woude GF, Cooper JA . 1993 Mol. Cell. Biol. 13: 2546–2553

  • Proud CG . 1995 Trends Biochem. Sci. 20: 241–246

  • Rhodes N, Innes CL, Propst F, Paules RS . 1997 Oncogene 14: 3017–3027

  • Rivas C, Gil J, Esteban M . 1999 J. Interferon Cytokine Res. 19: 1229–1236

  • Roy LM, Singh B, Gautier J, Arlinghaus RB, Nordeen SK, Maller JL . 1990 Cell 61: 825–831

  • Salzberg S, Vilchik S, Cohen S, Heller A, Kronfeld-Kinar Y . 2000 Exp. Cell Res. 254: 45–54

  • Shang Y, Baumrucker CR, Green MH . 1998 J. Biol. Chem. 273: 30608–30613

  • Singh B, Wittenberg C, Hannink M, Reed SI, Donoghue D, Arlinghaus RB . 1988 Virology 164: 114–120

  • Singh C, Haines GK, Talamonti MS, Radosevich JA . 1997 Tumour Biol. 16: 281–289

  • Squire J, Meurs EF, Chong KL, M cMillan NA, Hovanessian AG, Williams BR . 1993 Genomics 16: 768–770

  • Tan SL, Katze MG . 1999 J. Interferon Cytokine Res. 19: 543–554

  • Ueda K, Miyoshi Y, Tokino T, Watatani M, Nakamura Y . 1999 Oncol. Res. 11: 125–132

  • Vojdani A, Choneum M, Choppa PC, Magtoto L, Lapp CW . 1997 J. Intern. Med. 242: 465–478

  • Williams BR . 1999 Oncogene 18: 6112–6120

  • Williams BRG . 1995 Semin. Virol. 6: 191–202

  • Yeung NC, Lau AS . 1998 J. Biol. Chem. 273: 25198–25202

  • Yoshida N, Mita K, Yamashita M . 2000 Mol. Reprod. Dev. 57: 88–98

  • Zamanian-Daryoush M, Der SD, Williams BR . 1999 Oncogene 18: 315–326

Download references

Acknowledgements

We thank Uri Karo for his help with the flow-cytometry analysis and Avrille Goldreich for typing this manuscript. This work was supported by research grants from the Israel Cancer Research fund, the Israel Cancer Association (Melul Foundation, in memory of the late Prof N Trainin) and the CapCURE Research fund.

Author information

Author notes

  1. Samuel Salzberg: Deceased (1940–2000)

Authors and Affiliations

  1. Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 52900, Israel

    Yossi Dagon, Sara Dovrat, Shlomit Vilchik, Dalia Hacohen, Gilat Shlomo, Benjamin Sredni, Samuel Salzberg & Uri Nir

Authors
  1. Yossi Dagon
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sara Dovrat
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shlomit Vilchik
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Dalia Hacohen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Gilat Shlomo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Benjamin Sredni
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Samuel Salzberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Uri Nir
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Uri Nir.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dagon, Y., Dovrat, S., Vilchik, S. et al. Double-stranded RNA-dependent protein kinase, PKR, down-regulates CDC2/cyclin B1 and induces apoptosis in non-transformed but not in v-mos transformed cells. Oncogene 20, 8045–8056 (2001). https://doi.org/10.1038/sj.onc.1204945

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1204945

Keywords

This article is cited by

Search

Advanced search

Quick links