title: Thrombospondin-1 mediates oncogenic Ras-induced senescence in premalignant lung tumors.
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.
authors.forename: Kwan-Hyuck
authors.initials: KH
authors.lastname: Baek
authors.forename: Dongha
authors.initials: D
authors.lastname: Bhang
authors.forename: Alexander
authors.initials: A
authors.lastname: Zaslavsky
authors.forename: Liang-Chuan
authors.initials: LC
authors.lastname: Wang
authors.forename: Anil
authors.initials: A
authors.lastname: Vachani
authors.forename: Carla F
authors.initials: CF
authors.lastname: Kim
authors.forename: Steven M
authors.initials: SM
authors.lastname: Albelda
authors.forename: Gerard I
authors.initials: GI
authors.lastname: Evan
authors.forename: Sandra
authors.initials: S
authors.lastname: Ryeom
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000236:Adenoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism*; D016922:Cellular Senescence; D004848:Epithelium / Q000378:metabolism / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020935:MAP Kinase Signaling System; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020125:Mutation, Missense; D011230:Precancerous Conditions / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D021381:Protein Transport; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics* / Q000378:metabolism; D019700:Thrombospondin 1 / Q000502:physiology*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D019700:Thrombospondin 1; D016159:Tumor Suppressor Protein p53; D048049:Extracellular Signal-Regulated MAP Kinases; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)
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