Abstract 4353: Tristetraprolin (TTP) mediates radiation-induced TNF-α production in lung macrophages

Abstract The efficacy of radiation therapy for lung cancer is limited by radiation-induced lung toxicity (RILT). Although tumor necrosis factor-alpha (TNF-α) signaling plays a critical role in RILT, the molecular regulators of radiation-induced TNF-α production remain unknown. We investigated the role of a major TNF-α regulator, Tristetraprolin (TTP), in radiation-induced TNF-α production by lung macrophages. Tristetraprolin (TTP), an adenosine-uridine (AU) rich element (ARE) associated RNA binding protein, is known to destabilize TNF-α mRNA during lipopolysaccharide-induced inflammatory response and now we have identified that radiation causes TTP inactivation via inhibitory (Ser178) phosphorylation and induction of proteasome-mediated degradation, leading to increased TNF-α mRNA stability and secretion. Our preliminary studies indicate possible involvements of PI3K and p38 signaling in radiation-induced inactivating phosphorylation of TTP and we further identify an ubiquitin ligase [Skp-Cullin-F-box (SCFα-TrCP)] responsible for controlling radiation-induced TTP protein stability. These findings suggest that agents capable of blocking TTP phosphorylation or stabilizing TTP after irradiation could decrease RILT. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4353. doi:1538-7445.AM2012-4353