Abstract
Progression of premalignant lesions is restrained by oncogene-induced senescence. Oncogenic Ras triggers senescence in many organs, including the lung, which exhibits high levels of the angiogenesis inhibitor thrombospondin-1 (TSP-1). The contribution of TSP-1 upregulation to the modulation of tumorigenesis in the lung is unclear. Using a mouse model of lung cancer, we have shown that TSP-1 plays a critical and cell-autonomous role in suppressing Kras-induced lung tumorigenesis independent of its antiangiogenic function. Overall survival was decreased in a Kras-driven mouse model of lung cancer on a Tsp-1-/- background. We found that oncogenic Kras-induced TSP-1 upregulation in a p53-dependent manner. TSP-1 functioned in a positive feedback loop to stabilize p53 by interacting directly with activated ERK. TSP-1 tethering of ERK in the cytoplasm promoted a level of MAPK signaling that was sufficient to sustain p53 expression and a senescence response. Our data identify TSP-1 as a p53 target that contributes to maintaining Ras-induced senescence in the lung.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenocarcinoma / genetics
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Adenocarcinoma / metabolism*
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Adenocarcinoma / pathology
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Adenoma / genetics
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Adenoma / metabolism*
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Adenoma / pathology
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Animals
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Carcinogenesis / genetics
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Carcinogenesis / metabolism*
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Cellular Senescence
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Epithelium / metabolism
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Epithelium / pathology
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Gene Expression Regulation, Neoplastic
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Humans
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Lung / metabolism
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Lung / pathology
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Lung Neoplasms / genetics
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Lung Neoplasms / metabolism*
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Lung Neoplasms / pathology
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MAP Kinase Signaling System
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Mice
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Mice, 129 Strain
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Mice, Inbred C57BL
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Mice, Transgenic
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Mutation, Missense
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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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Protein Transport
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Proto-Oncogene Proteins p21(ras) / genetics*
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Proto-Oncogene Proteins p21(ras) / metabolism
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Thrombospondin 1 / physiology*
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Tumor Cells, Cultured
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Tumor Suppressor Protein p53 / metabolism
Substances
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Thrombospondin 1
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Tumor Suppressor Protein p53
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Extracellular Signal-Regulated MAP Kinases
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Hras protein, mouse
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Proto-Oncogene Proteins p21(ras)