NF-?B1 p105 suppresses lung tumorigenesis through the Tpl2 kinase but independently of its NF-?B function.

ABSTRACT: Nuclear factor-?B (NF-?B) is generally believed to be pro-tumorigenic. Here we report a tumor-suppressive function for NF-?B1, the prototypical member of NF-?B. While NF-?B1 downregulation is associated with high lung cancer risk in humans and poor patient survival, NF-?B1-deficient mice are more vulnerable to lung tumorigenesis induced by the smoke carcinogen, urethane. Notably, the tumor-suppressive function of NF-?B1 is independent of its classical role as an NF-?B factor, but instead through stabilization of the Tpl2 kinase. NF-?B1-deficient tumors exhibit 'normal' NF-?B activity, but a decreased protein level of Tpl2. Reconstitution of Tpl2 or the NF-?B1 p105, but not p50 (the processed product of p105), inhibits the tumorigenicity of NF-?B1-deficient lung tumor cells. Remarkably, Tpl2-knockout mice resemble NF-?B1 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-?B-independent but Tpl2-depenednt role of NF-?B1 in lung tumor suppression. These studies also reveal a previously unexplored role of p105/Tpl2 signaling in lung homeostasis.

SUBMITTER: Sun F 

PROVIDER: S-EPMC4548811 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature