NF-κB1 p105 suppresses lung tumorigenesis through the Tpl2 kinase but independently of its NF-κB function

Oncogene. 2016 May 5;35(18):2299-310. doi: 10.1038/onc.2015.299. Epub 2015 Aug 24.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinogenesis* / chemically induced
  • Carcinogenesis* / genetics
  • 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
  • Lung Neoplasms / pathology*
  • MAP Kinase Kinase Kinases / deficiency
  • MAP Kinase Kinase Kinases / genetics
  • MAP Kinase Kinase Kinases / metabolism*
  • Mice
  • Mutation
  • NF-kappa B p50 Subunit / deficiency
  • NF-kappa B p50 Subunit / genetics
  • NF-kappa B p50 Subunit / metabolism*
  • Proto-Oncogene Proteins / deficiency
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Urethane / pharmacology


  • NF-kappa B p50 Subunit
  • Proto-Oncogene Proteins
  • Urethane
  • MAP Kinase Kinase Kinases
  • MAP3K8 protein, human