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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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ADP-Ribosylation Factors / metabolism
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Animals
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Cell Cycle Proteins / metabolism
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Cell Proliferation
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Cell Transformation, Neoplastic / drug effects
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Cell Transformation, Neoplastic / genetics
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Cell Transformation, Neoplastic / metabolism*
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Cell Transformation, Neoplastic / pathology
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Cellular Senescence* / drug effects
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Cellular Senescence* / genetics
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Cyclin-Dependent Kinase Inhibitor p16 / metabolism
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Dose-Response Relationship, Drug
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Doxycycline / pharmacology
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Epithelial Cells / drug effects
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Epithelial Cells / metabolism*
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Epithelial Cells / pathology
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Female
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Gene Expression Regulation, Neoplastic
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Hyperplasia
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Mammary Glands, Animal / drug effects
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Mammary Glands, Animal / metabolism*
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Mammary Glands, Animal / pathology
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Mammary Neoplasms, Experimental / genetics
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Mammary Neoplasms, Experimental / metabolism*
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Mammary Neoplasms, Experimental / pathology
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Mice
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Mice, Transgenic
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Mutation
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Oncogene Protein p21(ras) / genetics
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Oncogene Protein p21(ras) / metabolism*
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Precancerous Conditions / genetics
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Precancerous Conditions / metabolism*
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Precancerous Conditions / pathology
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Promoter Regions, Genetic / drug effects
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Protein Transport
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Receptors, Estrogen / metabolism
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Receptors, Progesterone / metabolism
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Signal Transduction
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Time Factors
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Tumor Suppressor Protein p53 / metabolism
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Up-Regulation
Substances
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Cell Cycle Proteins
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Cyclin-Dependent Kinase Inhibitor p16
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Receptors, Estrogen
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Receptors, Progesterone
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Tumor Suppressor Protein p53
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ADP-Ribosylation Factors
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Oncogene Protein p21(ras)
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Doxycycline