期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 123, 期 10, 页码 4375-4389出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI67465
关键词
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资金
- Samsung Biomedical Research Institute [SBRI B-B00-08-3]
- V Foundation for Cancer Research
- American Cancer Society Research Scholar Grant
- NIH [P01CA66726, R01CA118375, P01CA45548]
- NCI/NIH [CA100193]
- Garrett B. Smith Foundation
- Ted Driven Foundation
- Cancer Research UK [12077] Funding Source: researchfish
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.
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