Baek, Kwan-HyuckBhang, DonghaZaslavsky, AlexanderWang, Liang-ChuanVachani, AnilKim, CarlaAlbelda, Steven M.Evan, Gerard I.Ryeom, Sandra2021-03-222013-09-09Baek KH, Bhang D, Zaslavsky A, Wang LC, Vachani A, Kim CF, Albelda SM, Evan GI, Ryeom S. 2013. Thrombospondin-1 Mediates Oncogenic Ras–induced Senescence in Premalignant Lung Tumors. Journal of Clinical Investigation 123, no. 10: 4375-89.0021-9738https://nrs.harvard.edu/URN-3:HUL.INSTREPOS:37367084Progression 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 throm- bospondin-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 sur- vival 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 feed- back 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.en-USJournal Article2021-03-2210.1172/jci67465