| First Author | Sun F | Year | 2016 |
| Journal | Oncogene | Volume | 35 |
| Issue | 18 | Pages | 2299-310 |
| PubMed ID | 26300007 | Mgi Jnum | J:234206 |
| Mgi Id | MGI:5789488 | Doi | 10.1038/onc.2015.299 |
| Citation | Sun F, et al. (2016) NF-kappaB1 p105 suppresses lung tumorigenesis through the Tpl2 kinase but independently of its NF-kappaB function. Oncogene 35(18):2299-310 |
| abstractText | Nuclear factor-kappaB (NF-kappaB) is generally believed to be pro-tumorigenic. Here we report a tumor-suppressive function for NF-kappaB1, the prototypical member of NF-kappaB. While NF-kappaB1 downregulation is associated with high lung cancer risk in humans and poor patient survival, NF-kappaB1-deficient mice are more vulnerable to lung tumorigenesis induced by the smoke carcinogen, urethane. Notably, the tumor-suppressive function of NF-kappaB1 is independent of its classical role as an NF-kappaB factor, but instead through stabilization of the Tpl2 kinase. NF-kappaB1-deficient tumors exhibit 'normal' NF-kappaB activity, but a decreased protein level of Tpl2. Reconstitution of Tpl2 or the NF-kappaB1 p105, but not p50 (the processed product of p105), inhibits the tumorigenicity of NF-kappaB1-deficient lung tumor cells. Remarkably, Tpl2-knockout mice resemble NF-kappaB1 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-kappaB-independent but Tpl2-depenednt role of NF-kappaB1 in lung tumor suppression. These studies also reveal a previously unexplored role of p105/Tpl2 signaling in lung homeostasis. |
