title: Escape from premature senescence is not sufficient for oncogenic transformation by Ras.
abstract: Resistance of primary cells to transformation by oncogenic Ras has been attributed to the induction of replicative growth arrest. This irreversible 'fail-safe mechanism' resembles senescence and requires induction by Ras of p19ARF and p53 (refs 3-5). Mutation of either p19ARF or p53 alleviates Ras-induced senescence and facilitates oncogenic transformation by Ras. Here we report that, whereas Rb and p107 are each dispensable for Ras-induced replicative arrest, simultaneous ablation of both genes disrupts Ras-induced senescence and results in unrestrained proliferation. This occurs despite activation by Ras of the p19ARF /p53 pathway, identifying pRb and p107 as essential mediators of Ras-induced antiproliferative p19ARF/p53 signalling. Unexpectedly, in contrast to p19ARF or p53 deficiency, loss of Rb/p107 function does not result in oncogenic transformation by Ras, as Ras-expressing Rb-/-/p107-/- fibroblasts fail to grow anchorage-independently in vitro and are not tumorigenic in vivo. These results demonstrate that in the absence of both Rb and p107 cells are resistant to p19ARF/p53-dependent protection against Ras-induced proliferation, and uncouple escape from Ras-induced premature senescence from oncogenic transformation.
authors.affiliation: Division of Molecular Carcinogenesis and Center for Biomedical Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: D S
authors.initials: DS
authors.lastname: Peeper
authors.forename: J H
authors.initials: JH
authors.lastname: Dannenberg
authors.forename: S
authors.initials: S
authors.lastname: Douma
authors.forename: H
authors.initials: H
authors.lastname: te Riele
authors.forename: R
authors.initials: R
authors.lastname: Bernards
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002455:Cell Division; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics / Q000502:physiology; D005347:Fibroblasts; D005786:Gene Expression Regulation; D016161:Genes, Retinoblastoma; D011905:Genes, ras; D006131:Growth Inhibitors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D050720:Retinoblastoma-Like Protein p107; D012190:Retroviridae / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D006131:Growth Inhibitors; D009687:Nuclear Proteins; D011506:Proteins; C493844:RBL1 protein, human; C489485:Rbl1 protein, mouse; D050720:Retinoblastoma-Like Protein p107; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53