Transcriptomal profiling of the cellular transformation induced by Rho subfamily GTPases.
We have used microarray technology to identify the transcriptional targets of Rho subfamily guanosine 5'-triphosphate (GTP)ases in NIH3T3 cells. This analysis indicated that murine fibroblasts transformed by these proteins show similar transcriptomal profiles. Functional annotation of the regulated genes indicate that Rho subfamily GTPases target a wide spectrum of functions, although loci encoding proteins linked to proliferation and DNA synthesis/transcription are upregulated preferentially. Rho proteins promote four main networks of interacting proteins nucleated around E2F, c-Jun, c-Myc and p53. Of those, E2F, c-Jun and c-Myc are essential for the maintenance of cell transformation. Inhibition of Rock, one of the main Rho GTPase targets, leads to small changes in the transcriptome of Rho-transformed cells. Rock inhibition decreases c-myc gene expression without affecting the E2F and c-Jun pathways. Loss-of-function studies demonstrate that c-Myc is important for the blockage of cell-contact inhibition rather than for promoting the proliferation of Rho-transformed cells. However, c-Myc overexpression does not bypass the inhibition of cell transformation induced by Rock blockage, indicating that c-Myc is essential, but not sufficient, for Rock-dependent transformation. These results reveal the complexity of the genetic program orchestrated by the Rho subfamily and pinpoint protein networks that mediate different aspects of the malignant phenotype of Rho-transformed cells.
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Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer (IBMCC), CSIC-University of Salamanca, Campus Unamuno, Salamanca, Spain.
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D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D050684:E2F Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D020869:Gene Expression Profiling; D051379:Mice; D005810:Multigene Family / Q000235:genetics*; D041681:NIH 3T3 Cells; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D018631:ras Proteins / Q000502:physiology; D020741:rho GTP-Binding Proteins / Q000235:genetics* / Q000502:physiology; D020742:rhoA GTP-Binding Protein / Q000502:physiology; D020743:rhoB GTP-Binding Protein / Q000502:physiology; D000075024:rhoC GTP-Binding Protein
D050684:E2F Transcription Factors; C489428:Myc protein, mouse; D016755:Proto-Oncogene Proteins c-jun; D016271:Proto-Oncogene Proteins c-myc; C512911:Rhoc protein, mouse; D018631:ras Proteins; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein; D020743:rhoB GTP-Binding Protein; D000075024:rhoC GTP-Binding Protein