Thrombospondin-1 mediates oncogenic Ras–induced senescence in premalignant lung tumors
Kwan-Hyuck Baek, … , Gerard I. Evan, Sandra Ryeom
Kwan-Hyuck Baek, … , Gerard I. Evan, Sandra Ryeom
Published September 9, 2013
Citation Information: J Clin Invest. 2013;123(10):4375-4389. https://doi.org/10.1172/JCI67465.
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Research Article Oncology

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

Kwan-Hyuck Baek, Dongha Bhang, Alexander Zaslavsky, Liang-Chuan Wang, Anil Vachani, Carla F. Kim, Steven M. Albelda, Gerard I. Evan, Sandra Ryeom

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Figure 7

Pharmacologic attenuation of ERK activity suppresses oncogenic Ras–induced senescence.

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Pharmacologic attenuation of ERK activity suppresses oncogenic Ras–induc...
(A) WT adult lung fibroblasts were infected with HrasV12 retrovirus, treated with the MEK inhibitor U0126 at the indicated concentrations, and stained for SA–β-gal activity. Percent SA–β-gal–positive cells was also quantified. Data represent mean ± SEM. Scale bars: 200 μm. (B) WT lung fibroblasts infected with HrasV12 retrovirus were treated with U0126 at the indicated concentrations for 3 days and probed for pERK, ERK, p19ARF, p53, and p21cip1 by immunoblotting. (C) A p53-dependent positive feedback role for TSP-1 in the maintenance of oncogenic Ras–induced senescence by tethering pERK in the cytoplasm.