The DOI matches its Crossref record; 35 of the 35 references it cites were found in a registry or an index.
Neutrophil elastase–mediated degradation of IRS-1 accelerates lung tumor growth
Open accessAbstract
Lung cancer is the leading cause of cancer death worldwide. Recent data suggest that tumor-associated inflammatory cells may modify lung tumor growth and invasiveness. To determine the role of neutrophil elastase (encoded by Elane) on tumor progression, we used the loxP-Stop-loxP K-rasG12D (LSL–K-ras) model of mouse lung adenocarcinoma to generate LSL–K-ras-Elane−/− mice. Tumor burden was markedly reduced in LSL–K-ras-Elane−/− mice at all time points after induction of mutant K-ras expression. Kaplan-Meier survival analysis showed that whereas all LSL–K-ras-Elane+/+ mice died, none of the mice lacking neutrophil elastase died. Neutrophil elastase directly induced tumor cell proliferation in both human and mouse lung adenocarcinomas by gaining access to an endosomal compartment within tumor cells, where it degraded insulin receptor substrate-1 (IRS-1). Immunoprecipitation studies showed that, as neutrophil elastase degraded IRS-1, there was increased interaction between phosphatidylinositol 3-kinase (PI3K) and the potent mitogen platelet-derived growth factor receptor (PDGFR), thereby skewing the PI3K axis toward tumor cell proliferation. The inverse relationship identified between neutrophil elastase and IRS-1 in LSL–K-ras mice was also identified in human lung adenocarcinomas, thus translating these findings to human disease. This study identifies IRS-1 as a key regulator of PI3K within malignant cells. Additionally, to our knowledge, this is the first description of a secreted proteinase gaining access to the inside of a cell and altering intracellular signaling.
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Cites
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Dynasore, a Cell-Permeable Inhibitor of Dynamin
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Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis
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Positive and negative regulation of insulin signaling through IRS-1 phosphorylation
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“The phosphorylation status of IRS-1 may dictate its behavior, with tyrosine-phosphorylated IRS-1 functioning as a positive effector of growth factor and serine-phosphorylated IRS-1 functioning as a regulatory facto”
BackgroundRas-induced interleukin-8 expression plays a critical role in tumor growth and angiogenesis
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Mice lacking neutrophil elastase reveal impaired host defense against gram negative bacterial sepsis
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Self-citation
Cited by
Coordinated regulation of myeloid cells by tumours
Gabrilovich, D. I., Ostrand-Rosenberg, S., & Bronte, V. (2012) · Nature Reviews Immunology · doi:10.1038/nri3175 · Cited by 3,544
Neutrophil extracellular traps in immunity and disease
Papayannopoulos, V. (2018) · Nature Reviews Immunology · doi:10.1038/nri.2017.105 · Cited by 3,397
Neutrophils in the activation and regulation of innate and adaptive immunity
Mantovani, A., Cassatella, M. A., Costantini, C., & Jaillon, S. (2011) · Nature Reviews Immunology · doi:10.1038/nri3024 · Cited by 3,027
Roles of the immune system in cancer: From tumor initiation to metastatic progression
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Neutrophils in cancer: Neutral no more
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Metadata
- Authors
- Houghton, A. M., Rzymkiewicz, D. M., Ji, H., Gregory, A. D., Egea, E. E., Metz, H. E., Stolz, D. B., Land, S. R., Marconcini, L. A., Kliment, C. R., Jenkins, K. M., Beaulieu, K. A., Mouded, M., Frank, S. J., Wong, K. K., & Shapiro, S. D.
- Venue
- Nature Medicine
- Published
- 2010-01-17
- Volume
- 16
- Issue
- 2
- Pages
- 219-223
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W2098888044
- Cited by
- 744
- References
- 35
- FWCI
- 7.50
- Type
- journal article
- Language
- en
- Open access
- green
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- Houghton, A. M., Rzymkiewicz, D. M., Ji, H., Gregory, A. D., Egea, E. E., Metz, H. E., Stolz, D. B., Land, S. R., Marconcini, L. A., Kliment, C. R., Jenkins, K. M., Beaulieu, K. A., Mouded, M., Frank, S. J., Wong, K. K., & Shapiro, S. D. (2010). Neutrophil elastase–mediated degradation of IRS-1 accelerates lung tumor growth. Nature Medicine. https://doi.org/10.1038/nm.2084
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