title: Dose-dependent oncogene-induced senescence in vivo and its evasion during mammary tumorigenesis.
abstract: Activating Ras mutations can induce either proliferation or senescence depending on the cellular context. To determine whether Ras activation has context-dependent effects in the mammary gland, we generated doxycycline-inducible transgenic mice that permit Ras activation to be titrated. Low levels of Ras activation - similar to those found in non-transformed mouse tissues expressing endogenous oncogenic Kras2 - stimulate cellular proliferation and mammary epithelial hyperplasias. In contrast, high levels of Ras activation - similar to those found in tumours bearing endogenous Kras2 mutations - induce cellular senescence that is Ink4a-Arf- dependent and irreversible following Ras downregulation. Chronic low-level Ras induction results in tumour formation, but only after the spontaneous upregulation of activated Ras and evasion of senescence checkpoints. Thus, high-level, but not low-level, Ras activation activates tumour suppressor pathways and triggers an irreversible senescent growth arrest in vivo. We suggest a three-stage model for Ras-induced tumorigenesis consisting of an initial activating Ras mutation, overexpression of the activated Ras allele and, finally, evasion of p53-Ink4a-Arf-dependent senescence checkpoints.
authors: Department of Cancer Biology, The Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6160, USA.
authors: Christopher J
authors: CJ
authors: Sarkisian
authors: Blaine A
authors: BA
authors: Keister
authors: Douglas B
authors: DB
authors: Stairs
authors: Robert B
authors: RB
authors: Boxer
authors: Susan E
authors: SE
authors: Moody
authors: Lewis A
authors: LA
authors: Chodosh
mesh_terms: D020727:ADP-Ribosylation Factors / Q000378:metabolism; D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016922:Cellular Senescence / Q000187:drug effects / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004318:Doxycycline / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006965:Hyperplasia; D008321:Mammary Glands, Animal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D015689:Oncogene Protein p21(ras) / Q000235:genetics / Q000378:metabolism*; D011230:Precancerous Conditions / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000187:drug effects; D021381:Protein Transport; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D018797:Cell Cycle Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D016159:Tumor Suppressor Protein p53; D020727:ADP-Ribosylation Factors; D015689:Oncogene Protein p21(ras); D004318:Doxycycline