The DOI matches its Crossref record; 38 of the 38 references it cites were found in a registry or an index.
An NF-κB pathway–mediated positive feedback loop amplifies Ras activity to pathological levels in mice
Open accessAbstract
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.
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Cites
Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse
Hingorani, S. R., Petricoin, E. F., Maitra, A., Rajapakse, V., King, C., Jacobetz, M. A., Ross, S., Conrads, T. P., Veenstra, T. D., Hitt, B. A., et al. (2003) · Cancer Cell · doi:10.1016/s1535-6108(03)00309-x · Cited by 2,471
Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras
Jackson, E. L., Willis, N., Mercer, K., Bronson, R. T., Crowley, D., Montoya, R., Jacks, T., & Tuveson, D. A. (2001) · Genes & Development · doi:10.1101/gad.943001 · Cited by 1,898
Guerra, C., Schuhmacher, A. J., Cañamero, M., Grippo, P. J., Verdaguer, L., Pérez-Gallego, L., Dubus, P., Sandgren, E. P., & Barbacid, M. (2007) · Cancer Cell · doi:10.1016/j.ccr.2007.01.012 · Cited by 1,224
Liddle, R. A., Goldfine, I. D., Rosen, M. S., Taplitz, R. A., & Williams, J. A. (1985) · Journal of Clinical Investigation · doi:10.1172/jci111809 · Cited by 745
Bardeesy, N., Aguirre, A. J., Chu, G. C., Cheng, K.-H., Lopez, L. V., Hezel, A. F., Feng, B., Brennan, C., Weissleder, R., Mahmood, U., et al. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0601273103 · Cited by 581
Tumor induction by an endogenous K-ras oncogene is highly dependent on cellular context
Guerra, C., Mijimolle, N., Dhawahir, A., Dubus, P., Barradas, M., Serrano, M., Campuzano, V., & Barbacid, M. (2003) · Cancer Cell · doi:10.1016/s1535-6108(03)00191-0 · Cited by 571
Guanosine Triphosphatase Activating Protein (GAP) Interacts with the p21 ras Effector Binding Domain
Adari, H., Lowy, D. R., Willumsen, B. M., Der, C. J., & McCormick, F. (1988) · Science · doi:10.1126/science.2833817 · Cited by 506
Dose-dependent oncogene-induced senescence in vivo and its evasion during mammary tumorigenesis
Sarkisian, C. J., Keister, B. A., Stairs, D. B., Boxer, R. B., Moody, S. E., & Chodosh, L. A. (2007) · Nature Cell Biology · doi:10.1038/ncb1567 · Cited by 490
Early NF-κB activation is associated with hormone-induced pancreatitis
Gukovsky, I., Gukovskaya, A. S., Blinman, T. A., Zaninovic, V., & Pandol, S. J. (1998) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.1998.275.6.g1402 · Cited by 344
Coppé, J.-P., Patil, C. K., Rodier, F., Sun, Y., Muñoz, D. P., Goldstein, J., Nelson, P. S., Desprez, P.-Y., & Campisi, J. (2008) · PLoS Biology · doi:10.1371/journal.pbio.0060301 · Cited by 302 · cited 1×
“Inflammatory stimuli induced prolonged elevation of active Ras in the presence of oncogenic Ras (current study), and high sustained Ras activity generates inflammatory mediators (10, 18).”
Cited by
Steele, C. W., Karim, S. A., Leach, J. D. G., Bailey, P., Upstill-Goddard, R., Rishi, L., Foth, M., Bryson, S., McDaid, K., Wilson, Z., et al. (2016) · Cancer Cell · doi:10.1016/j.ccell.2016.04.014 · Cited by 845
A Starring Role for Stellate Cells in the Pancreatic Cancer Microenvironment
Apte, M. V., Wilson, J. S., Lugea, A., & Pandol, S. J. (2013) · Gastroenterology · doi:10.1053/j.gastro.2012.11.037 · Cited by 450
Immune modulatory effects of oncogenic KRAS in cancer
Hamarsheh, S., Groß, O., Brummer, T., & Zeiser, R. (2020) · Nature Communications · doi:10.1038/s41467-020-19288-6 · Cited by 387
Roles for KRAS in Pancreatic Tumor Development and Progression
di Magliano, M. P., & Logsdon, C. D. (2013) · Gastroenterology · doi:10.1053/j.gastro.2013.01.071 · Cited by 400
Self-citationMacrophage-secreted cytokines drive pancreatic acinar-to-ductal metaplasia through NF-κB and MMPs
Liou, G.-Y., Döppler, H., Necela, B., Krishna, M., Crawford, H. C., Raimondo, M., & Storz, P. (2013) · Journal of Cell Biology · doi:10.1083/jcb.201301001 · Cited by 294
Metadata
- Authors
- Daniluk, J., Liu, Y., Deng, D., Chu, J., Huang, H., Gaiser, S., Cruz-Monserrate, Z., Wang, H., Ji, B., & Logsdon, C. D.
- Venue
- Journal of Clinical Investigation
- Published
- 2012-04-02
- Volume
- 122
- Issue
- 4
- Pages
- 1519-1528
- ISSN
- 0021-9738 (ISSN-L)
- OpenAlex
- W2089784089
- Cited by
- 276
- References
- 38
- FWCI
- 7.64
- Type
- journal article
- Language
- en
- Open access
- bronze
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