The Rgr oncogene (homologous to RalGDS) induces transformation and gene expression by activating Ras, Ral and Rho mediated pathways.
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. Oncogene (2000).
Hernandez-Muñoz
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I
Department of Pathology and Kaplan Cancer Center, New York University Medical Center, New York, NY 10016, USA.
Malumbres
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M
Leonardi
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P
Pellicer
A
A
D016475:3T3 Cells; D000818:Animals; D002455:Cell Division / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D003599:Cytoskeleton / Q000235:genetics / Q000378:metabolism; D005136:Eye Proteins / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D016758:Genes, jun; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled; D020218:Response Elements; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D020725:ral GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D020726:ral Guanine Nucleotide Exchange Factor / Q000235:genetics* / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism
D005136:Eye Proteins; C089754:G protein-coupled receptor RGR; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D020726:ral Guanine Nucleotide Exchange Factor; D020928:Mitogen-Activated Protein Kinases; D020725:ral GTP-Binding Proteins; D018631:ras Proteins; D020741:rho GTP-Binding Proteins