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An NF-κB pathway–mediated positive feedback loop amplifies Ras activity to pathological levels in mice
Jaroslaw Daniluk, … , Baoan Ji, Craig D. Logsdon
Jaroslaw Daniluk, … , Baoan Ji, Craig D. Logsdon
Published March 12, 2012
Citation Information: J Clin Invest. 2012;122(4):1519-1528. https://doi.org/10.1172/JCI59743.
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Research Article Oncology Article has an altmetric score of 8

An NF-κB pathway–mediated positive feedback loop amplifies Ras activity to pathological levels in mice

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Abstract

Genetic mutations that give rise to active mutant forms of Ras are oncogenic and found in several types of tumor. However, such mutations are not clear biomarkers for disease, since they are frequently detected in healthy individuals. Instead, it has become clear that elevated levels of Ras activity are critical for Ras-induced tumorigenesis. However, the mechanisms underlying the production of pathological levels of Ras activity are unclear. Here, we show that in the presence of oncogenic Ras, inflammatory stimuli initiate a positive feedback loop involving NF-κB that further amplifies Ras activity to pathological levels. Stimulation of Ras signaling by typical inflammatory stimuli was transient and had no long-term sequelae in wild-type mice. In contrast, these stimuli generated prolonged Ras signaling and led to chronic inflammation and precancerous pancreatic lesions (PanINs) in mice expressing physiological levels of oncogenic K-Ras. These effects of inflammatory stimuli were disrupted by deletion of inhibitor of NF-κB kinase 2 (IKK2) or inhibition of Cox-2. Likewise, expression of active IKK2 or Cox-2 or treatment with LPS generated chronic inflammation and PanINs only in mice expressing oncogenic K-Ras. The data support the hypothesis that in the presence of oncogenic Ras, inflammatory stimuli trigger an NF-κB–mediated positive feedback mechanism involving Cox-2 that amplifies Ras activity to pathological levels. Because a large proportion of the adult human population possesses Ras mutations in tissues including colon, pancreas, and lung, disruption of this positive feedback loop may be an important strategy for cancer prevention.

Authors

Jaroslaw Daniluk, Yan Liu, Defeng Deng, Jun Chu, Haojie Huang, Sebastian Gaiser, Zobeida Cruz-Monserrate, Huamin Wang, Baoan Ji, Craig D. Logsdon

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Figure 1

Stimuli induced prolonged increases in Ras activity in cells prepared from acinar-Ras but not control mice.

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Stimuli induced prolonged increases in Ras activity in cells prepared fr...
Freshly isolated acini from control or acinar-Ras mice were stimulated with 10 nM CCK-8 (A) or 1 μg/ml LPS (B) for different time periods. The GTP-bound active Ras was measured by a Raf pull-down assay. In each case, a representative Western blot is shown with quantitative data from n = 3–4 independent experiments (*P < 0.05 versus time 0).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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