title: Ras protects Rb family null fibroblasts from cell death: a role for AP-1.
abstract: The retinoblastoma protein (Rb) controls cell proliferation, differentiation, and senescence and provides an essential tumor suppressive function that cells must eliminate to attain unlimited proliferative potential. Elimination of the Rb pathway also results in apoptosis, however, thereby providing an efficient surveillance mechanism to sense the loss of Rb. To become tumorigenic cells must thus overcome not only Rb function but also the apoptotic response caused by the loss of Rb function. We show that oncogenic Ras (RasV12) potently blocks cell death in Rb family member knockout mouse embryo fibroblasts (TKO cells). Activation of phosphatidylinositol 3-kinase and Raf by oncogenic Ras mediated this protection, implying that multiple Ras effector pathways are required, in concert, for this pro-survival signal. Although activation of Raf by selective Ras mutants protected TKO cells from cell death, pharmacologic inhibition of MEK had little effect on RasV12 protection, suggesting that a Raf-dependent, MEK-independent pathway was important for this effect. We show that this Raf-dependent protection occurred through activation of c-Jun and thus AP-1 activation. These observations could account for the dependence of Ras transformation on c-Jun activity and for the roles of AP-1 in oncogenesis. Our results support the concept of two oncogenic events cooperating to achieve a balance between immortalization and survival.
authors.affiliation: Departments of Medicine and Cell Biology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: Arthur P
authors.initials: AP
authors.lastname: Young
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Longmore
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D016160:Retinoblastoma Protein / Q000235:genetics / Q000502:physiology*; D018808:Transcription Factor AP-1 / Q000502:physiology*; D018631:ras Proteins / Q000502:physiology*
chemical_list: D016160:Retinoblastoma Protein; D018808:Transcription Factor AP-1; D018631:ras Proteins