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 5

Sustained oncogenic Kras signaling is attenuated in the absence of TSP-1.

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Sustained oncogenic Kras signaling is attenuated in the absence of TSP-1...
(A) Western blot of ERK, p19ARF, and p16INK4a expression after KrasG12D activation in KrasG12D×Tsp-1+/+ and KrasG12D×Tsp-1–/– primary adult lung fibroblasts isolated at the indicated times after oncogenic Kras activation. β-actin served as loading control. (B) Immunofluorescence for p19ARF in KrasG12D×Tsp-1+/+ and KrasG12D×Tsp-1–/– lung sections isolated 21 weeks after KrasG12D activation. Hoechst stain indicates nuclei. Scale bars: 50 μm. (C) KrasG12D×Tsp-1+/+ and KrasG12D×Tsp-1–/– primary lung fibroblasts were infected with Ad-Cre, harvested at the indicated times, and probed for pMEK and total MEK by immunoblotting. β-actin served as loading control. (D) Tsp-1+/+ and Tsp-1–/– primary lung fibroblasts were infected with HrasV12 or mock retrovirus, harvested at the indicated times, and probed for TSP-1, pERK, total ERK, and p19ARF expression by immunoblotting. Uninfected lung fibroblasts were used as negative controls; β-actin served as loading control. (E) Tsp-1+/+ and Tsp-1–/– primary lung fibroblasts were treated with 10 nM EGF, harvested at the indicated times, and probed for TSP-1, pERK, and total ERK expression by immunoblotting. β-actin served as loading control.