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