title: Oncogenic Ha-Ras-induced signaling activates NF-kappaB transcriptional activity, which is required for cellular transformation.
abstract: Ras proteins function in stimulating cell proliferation and differentiation through the activation of Raf-dependent and Raf-independent signal transduction pathways and the subsequent activation of specific transcription factors. The transcription factor NF-kappaB has been widely studied as a regulator of genes involved in immune and inflammatory responses. A variety of stimuli activate NF-kappaB through the induced phosphorylation and degradation of the inhibitor IkappaB followed by nuclear translocation of NF-kappaB. We show here that oncogenic forms of Ha-Ras activate NF-kappaB, not through induced nuclear translocation, but rather through the activation of the transcriptional function of the NF-kappaB RelA/p65 subunit. Importantly, RelA/p65 -/- cells are inefficient in the activation of kappaB-dependent gene expression in response to oncogenic Ras expression. Furthermore, IkappaBalpha expression blocks focus formation in NIH3T3 cells induced by oncogenic Ras. These results demonstrate that NF-kappaB is a critical downstream mediator of Ha-Ras signaling and oncogenic potential.
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599-7295, USA.
authors.forename: T S
authors.initials: TS
authors.lastname: Finco
authors.forename: J K
authors.initials: JK
authors.lastname: Westwick
authors.forename: J L
authors.initials: JL
authors.lastname: Norris
authors.forename: A A
authors.initials: AA
authors.lastname: Beg
authors.forename: C J
authors.initials: CJ
authors.lastname: Der
authors.forename: A S
authors.initials: AS
authors.lastname: Baldwin
mesh_terms: D016475:3T3 Cells; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D015689:Oncogene Protein p21(ras) / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf; D015398:Signal Transduction; D051996:Transcription Factor RelA; D014158:Transcription, Genetic
chemical_list: D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D051996:Transcription Factor RelA; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf; D015689:Oncogene Protein p21(ras)