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 Rgr oncogene (homologous to RalGDS) induces transformation and gene expression by activating Ras, Ral and Rho mediated pathways

Oncogene volume 19, pages 2745–2757 (2000)Cite this article

Abstract

The effects of the 5′-truncated Rgr oncogene, a previously shown specific guanine exchange factor for Ral in vitro, in stimulating proliferation, cell transformation and gene expression were investigated. We have established TetRgr cell lines in which expression of Rgr can be inhibited by the presence of tetracycline in the medium. Using this system, we show that Rgr overexpressing cells are morphologically transformed and grow in a disorganized manner. At the transcriptional level, Rgr enhances the activity of the serum response element and c-Jun. Rgr induces phosphorylation of ERKs, p38 and JNK kinases, and increases the levels of the GTP-bound forms of Ral and Ras. Ras activation could account for the broad spectra of effects displayed by Rgr. The important role of these pathways is confirmed by experiments in which the transcriptional activation events can be blocked by dominant negative versions of Ras, Ral and Rho. Among all the Rgr-induced pathways, the Ras-Raf-MEK-ERK cascade is essential for the transforming properties of Rgr. Additional analysis has shown that the activation of this pathway by Rgr is not due to a feed back mechanism mediated by the Grb2 adaptor protein.

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 5
Figure 4
Figure 6
Figure 7
Figure 8
Figure 9
Figure 10
Figure 11
Figure 12

Similar content being viewed by others

References

  • Alexandropoulos K and Baltimore D . 1996 Genes Dev 10: 1341–1355

  • Aronheim A, Engelberg D, Li N, al-Alawi N, Schlessinger J and Karin M . 1994 Cell 78: 949–961

  • Boguski MS and McCormick F . 1993 Nature 366: 643–654

  • Bos JL . 1997 Biochim Biophys Acta 1333: M19–M31

  • Bos JL . 1998 EMBO J 17: 6776–6782

  • Campbell SL, Khosravi-Far R, Rossman KL, Clark GJ and Der CJ . 1998 Oncogene 17 11 Reviews: 1395–1413

  • Cantor SB, Urano T and Feig LA . 1995 Mol Cell Biol 15: 4578–4584

  • Chardin P and Tavitian A . 1989 Nucleic Acids Res 17: 4380

  • Chomczynski P and Sacchi N . 1987 Anal Biochem 162: 156–159

  • Cowley S, Paterson H, Kemp P and Marshall CJ . 1994 Cell 77: 841–852

  • D'Adamo DR, Novick S, Kahn JM, Leonardi P and Pellicer A . 1997 Oncogene 14: 1295–1305

  • Day GJ, Mosteller RD and Broek D . 1998 Mol Cell Biol 18: 7444–7454

  • Denhardt DT . 1996 Biochem J 318: 729–747

  • de Rooij J and Bos JL . 1997 Oncogene 14: 623–625

  • Feig LA and Cooper GM . 1988 Mol Cell Biol 8: 3235–3243

  • Franke B, Akkerman JWN and Bos JL . 1997 EMBO J 16: 252–259

  • Goi T, Rusanescu G, Urano T and Feig LA . 1999 Mol Cell Biol 19: 1731–1741

  • Gossen M and Bujard H . 1992 Proc Natl Acad Sci USA 89: 5547–5551

  • Gupta S, Campbell D, Derijard B and Davis RJ . 1995 Science 267: 389–393

  • Hill CS, Wynne J and Treisman R . 1995 Cell 81: 1159–1170

  • Ikeda M, Ishida O, Hinoi T, Kishida S and Kikuchi A . 1998 J Biol Chem 273: 814–821

  • Johnson PJ, Coussenns PM, Danko AV and Shalloway D . 1985 Mol Cell Biol 5: 1073–1083

  • Kerkhoff E, Houben R, Loffler S, Troppmair J, Lee JE and Rapp UR . 1998 Oncogene 16: 211–216

  • Khosravi-Far R, Solski PA, Clark GJ, Kinch MS and Der CJ . 1995 Mol Cell Biol 15: 6443–6453

  • Khosravi-Far R, Campbell S, Rossman KL and Der CJ . 1998 Advances in Cancer Res 72: 57–107

  • Lin R, Bagrodia S, Cerione R and Manor D . 1997 Curr Biol 7: 794–797

  • Lowenstein E, Daly RJ, Batzer A, Li N, Margolis B, Lammers R, Ullrich A, Skolnik EY, Bar-Sagi D and Schlessinger J . 1992 Cell 70: 431–442

  • Malumbres M and Pellicer A . 1998 Front Biosci 3: D887–D912

  • Mangues R, Corral T, Kohl NE, Symmans WF, Lu S, Malumbres M, Gibbs JB, Oliff A and Pellicer A . 1998 Cancer Res 58: 1253–1259

  • Martin-Zanca D, Oskam R, Mitra G, Copeland T and Barbacid M . 1989 Mol Cell Biol 9: 24–33

  • Murai H, Ikeda M, Kishida S, Ishida O, Okazaki-Kishida M, Matsuura Y and Kikuchi A . 1997 J Biol Chem 272: 10483–10490

  • Nimnual AS, Yatsula BA and Bar-Sagi D . 1998 Science 279: 560–563

  • Nobes CD and Hall A . 1995 Cell 81: 53–62

  • Price MA, Rogers AE and Treisman R . 1995 EMBO J 14: 2589–2601

  • Quilliam LA, Khosravi-Far R, Huff SY and Der CJ . 1995 Bioessays 17: 395–404

  • Rodriguez-Viciana P, Warne PH, Khwaja A, Marte BM, Pappin D, Das P, Waterfield MD, Ridley A and Downward J . 1997 Cell 89: 457–467

  • Sawamoto K, Winge P, Koyama S, Hirota Y, Yamada C, Miyao S, Yoshikawa S, Jin MH, Kikuchi A and Okano H . 1999 J Cell Biol 146: 361–372

  • Shaw PE, Schroter H and Nordheim A . 1989 Cell 56: 563–572

  • Skolnik EY, Batzer A, Li N, Lee C-H, Lowenstein E, Mohammadi M, Margolis B and Schlessinger J . 1993 Science 260: 1953–1955

  • Treisman R . 1994 Curr Opin Genet Dev 4: 96–101

  • Verheijen MH, Wolthuis RM, Defize LH, den Hertog J and Bos JL . 1999 Oncogene 18: 4435–4439

  • Vojtek AB and Cooper JA . 1995 Cell 82: 527–529

  • Westwick JK, Cox AD, Der CJ, Cobb MH, Hibi M, Karin M and Brenner DA . 1994 Proc Natl Acad Sci USA 91: 6030–6034

  • Westwick JK, Lambert QT, Clark GJ, Symons M, Van Aelst L, Pestell RG and Der CJ . 1997 Mol Cell Biol 17: 1324–1335

  • White MA, Nicolette C, Minden A, Polverino A, Van Aelst L, Karin M and Wigler MH . 1995 Cell 80: 533–541

  • White MA, Vale T, Camonis JH, Schaefer E and Wigler MH . 1996 J Biol Chem 271: 16439–16442

  • Whitehurst CE, Owaki H, Bruder JT, Rapp UR and Geppert TD . 1995 J Biol Chem 270: 5594–5599

  • Wigler M, Pellicer A, Silverstein S and Axel R . 1978 Cell 14: 725–731

  • Wolthuis RMF and Bos JL . 1999 Curr Opin Genet Dev 9: 112–117

  • Wolthuis RMF, Franke B, Van Triest M, Bauer B, Cool RH, Camonis JH, Akkerman J-WN and Bos JL . 1998a Mol Cell Biol 18: 2486–2491

  • Wolthuis RMF, de Ruiter ND, Cool RH and Bos JL . 1997 EMBO J 16: 6748–6761

  • Wolthuis RM, Zwartkruis F, Moen TC and Bos JL . 1998b Curr Biol 8: 471–474

  • Yamaguchi A, Urano T, Goi T and Feig LA . 1997 J Biol Chem 272: 31230–31234

Download references

Acknowledgements

We are grateful to Drs XR Bustelo, H Bujard, K Alexandropoulos, CJ Der, LA Feig, UR Rapp, CJ Marshall; RG Pestell, DA Brenner, RJ Davis, K Reif, J Schlessinger and JL Bos for the gift of expression and reporter plasmids. We would like to thank T Corral, M Calero and M Benet for their assistance in some of the experiments, Dr J Hirst for flow cytometry analysis, and Dr VK Tsiagbe for the luminometer. This research was supported by NIH Grants CA 50434 and CA 36327 to A Pellicer. I Hernandez-Muñoz and M Malumbres are recipients of Ministerio de Educacion y Ciencia (Spain) fellowships.

Author information

Authors and Affiliations

  1. Department of Pathology and Kaplan Cancer Center, New York University Medical Center, New York, 10016, NY, USA

    Inmaculada Hernandez-Muñoz, Marcos Malumbres, Peter Leonardi & Angel Pellicer

Authors
  1. Inmaculada Hernandez-Muñoz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marcos Malumbres
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Peter Leonardi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Angel Pellicer
    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

Hernandez-Muñoz, I., Malumbres, M., Leonardi, P. et al. The Rgr oncogene (homologous to RalGDS) induces transformation and gene expression by activating Ras, Ral and Rho mediated pathways. Oncogene 19, 2745–2757 (2000). https://doi.org/10.1038/sj.onc.1203586

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1203586

Keywords

This article is cited by

Search

Advanced search

Quick links