title: NF-κB1 p105 suppresses lung tumorigenesis through the Tpl2 kinase but independently of its NF-κB function.
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.
authors: University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.|Department of Microbiology and Molecular Genetics, Hillman Cancer Center Research Pavilion, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors: F
authors: F
authors: Sun
authors: University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.|Department of Microbiology and Molecular Genetics, Hillman Cancer Center Research Pavilion, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors: Z
authors: Z
authors: Qu
authors: University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.|Program of Biological Science, La Roche College, Pittsburgh, PA, USA.
authors: Y
authors: Y
authors: Xiao
authors: University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.|Department of Microbiology and Molecular Genetics, Hillman Cancer Center Research Pavilion, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors: J
authors: J
authors: Zhou
authors: University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors: T F
authors: TF
authors: Burns
authors: University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.|Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors: L P
authors: LP
authors: Stabile
authors: University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.|Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors: J M
authors: JM
authors: Siegfried
authors: University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.|Department of Microbiology and Molecular Genetics, Hillman Cancer Center Research Pavilion, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors: G
authors: G
authors: Xiao
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000139:chemically induced / Q000235:genetics; D045744:Cell Line, Tumor; D004795:Enzyme Stability / Q000187:drug effects / Q000235:genetics; D055786:Gene Knockout Techniques; D011905:Genes, ras / Q000235:genetics; D006706:Homeostasis / Q000187:drug effects / Q000235:genetics; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008175:Lung Neoplasms / Q000473:pathology*; D020930:MAP Kinase Kinase Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D052002:NF-kappa B p50 Subunit / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014520:Urethane / Q000494:pharmacology
chemical_list: D052002:NF-kappa B p50 Subunit; D011518:Proto-Oncogene Proteins; D014520:Urethane; D020930:MAP Kinase Kinase Kinases; C069937:MAP3K8 protein, human