title: Sam68/KHDRBS1-dependent NF-κB activation confers radioprotection to the colon epithelium in γ-irradiated mice.
abstract: Previously we reported that Src-associated-substrate-during-mitosis-of-68kDa (Sam68/KHDRBS1) is pivotal for DNA damage-stimulated NF-κB transactivation of anti-apoptotic genes (Fu et al., 2016). Here we show that Sam68 is critical for genotoxic stress-induced NF-κB activation in the γ-irradiated colon and animal and that Sam68-dependent NF-κB activation provides radioprotection to colon epithelium in vivo. Sam68 deletion diminishes γ-irradiation-triggered PAR synthesis and NF-κB activation in colon epithelial cells (CECs), thus hampering the expression of anti-apoptotic molecules in situ and facilitating CECs to undergo apoptosis in mice post whole-body γ-irradiation (WBIR). Sam68 knockout mice suffer more severe damage in the colon and succumb more rapidly from acute radiotoxicity than the control mice following WBIR. Our results underscore the critical role of Sam68 in orchestrating genotoxic stress-initiated NF-κB activation signaling in the colon tissue and whole animal and reveal the pathophysiological relevance of Sam68-dependent NF-κB activation in colonic cell survival and recovery from extrinsic DNA damage.
authors.affiliation: Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, United States.
authors.forename: Kai
authors.initials: K
authors.lastname: Fu
authors.affiliation: Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, United States.
authors.forename: Xin
authors.identifier: 0000-0003-2424-8011
authors.initials: X
authors.lastname: Sun
authors.affiliation: Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, United States.
authors.forename: Eric M
authors.initials: EM
authors.lastname: Wier
authors.affiliation: Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, United States.
authors.forename: Andrea
authors.initials: A
authors.lastname: Hodgson
authors.affiliation: Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, United States.
authors.forename: Ryan P
authors.initials: RP
authors.lastname: Hobbs
authors.affiliation: Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, United States.|Department of Oncology, School of Medicine, Johns Hopkins University, Baltimore, United States.|The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, United States.
authors.forename: Fengyi
authors.identifier: 0000-0001-9216-9767
authors.initials: F
authors.lastname: Wan
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D003106:Colon / Q000528:radiation effects*; D005720:Gamma Rays; D007413:Intestinal Mucosa / Q000528:radiation effects*; D018345:Mice, Knockout; D052002:NF-kappa B p50 Subunit / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C513253:Khdrbs1 protein, mouse; D052002:NF-kappa B p50 Subunit; D016601:RNA-Binding Proteins; C073701:Nfkb1 protein, mouse
keywords: KHDRBS1; NF-κB; Sam68; cancer biology; cell biology; colon epithelium; mouse; radiodamage