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J Clin Invest. 2013 Oct;123(10):4375-89. doi: 10.1172/JCI67465. Epub 2013 Sep 9.

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.

PMID:
24018559
PMCID:
PMC3784530
DOI:
10.1172/JCI67465
[Indexed for MEDLINE]
Free PMC Article

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