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NF-κB1 p105 suppresses lung tumorigenesis through the Tpl2 kinase but independently of its NF-κB function.
- Source :
-
Oncogene [Oncogene] 2016 May 05; Vol. 35 (18), pp. 2299-310. Date of Electronic Publication: 2015 Aug 24. - Publication Year :
- 2016
-
Abstract
- Nuclear factor-κB (NF-κB) is generally believed to be pro-tumorigenic. Here we report a tumor-suppressive function for NF-κB1, the prototypical member of NF-κB. While NF-κB1 downregulation is associated with high lung cancer risk in humans and poor patient survival, NF-κB1-deficient mice are more vulnerable to lung tumorigenesis induced by the smoke carcinogen, urethane. Notably, the tumor-suppressive function of NF-κB1 is independent of its classical role as an NF-κB factor, but instead through stabilization of the Tpl2 kinase. NF-κB1-deficient tumors exhibit 'normal' NF-κB activity, but a decreased protein level of Tpl2. Reconstitution of Tpl2 or the NF-κB1 p105, but not p50 (the processed product of p105), inhibits the tumorigenicity of NF-κB1-deficient lung tumor cells. Remarkably, Tpl2-knockout mice resemble NF-κB1 knockouts in urethane-induced lung tumorigenesis. Mechanistic studies indicate that p105/Tpl2 signaling is required for suppressing urethane-induced lung damage and inflammation, and activating mutations of the K-Ras oncogene. These studies reveal an unexpected, NF-κB-independent but Tpl2-depenednt role of NF-κB1 in lung tumor suppression. These studies also reveal a previously unexplored role of p105/Tpl2 signaling in lung homeostasis.
- Subjects :
- Animals
Cell Line, Tumor
Enzyme Stability drug effects
Enzyme Stability genetics
Gene Knockout Techniques
Genes, ras genetics
Homeostasis drug effects
Homeostasis genetics
Humans
Lung drug effects
Lung pathology
MAP Kinase Kinase Kinases deficiency
MAP Kinase Kinase Kinases genetics
Mice
Mutation
NF-kappa B p50 Subunit deficiency
NF-kappa B p50 Subunit genetics
Proto-Oncogene Proteins deficiency
Proto-Oncogene Proteins genetics
Signal Transduction drug effects
Signal Transduction genetics
Urethane pharmacology
Carcinogenesis chemically induced
Carcinogenesis genetics
Lung Neoplasms pathology
MAP Kinase Kinase Kinases metabolism
NF-kappa B p50 Subunit metabolism
Proto-Oncogene Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5594
- Volume :
- 35
- Issue :
- 18
- Database :
- MEDLINE
- Journal :
- Oncogene
- Publication Type :
- Academic Journal
- Accession number :
- 26300007
- Full Text :
- https://doi.org/10.1038/onc.2015.299