Sam68/KHDRBS1-dependent NF-κB activation confers radioprotection to the colon epithelium in γ-irradiated mice
- Johns Hopkins University, United States
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.
Article and author information
Author details
Funding
National Institute of General Medical Sciences (R01GM111682)
- Fengyi Wan
American Cancer Society (RSG-13-052-01-MPC)
- Fengyi Wan
National Cancer Institute (T32CA009110)
- Eric M Wier
National Cancer Institute (T32CA009110)
- Ryan P Hobbs
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All animal experiments were performed according to protocol number MO16-H285, approved by the Johns Hopkins University's Animal Care and Use Committee and in direct accordance with the NIH guidelines for housing and care of laboratory animals. Khdrbs1-/- mice and their gender-matched littermate Khdrbs1+/- mice were produced using heterozygous breeding pairs. Mice were maintained in a specific pathogen-free facility and fed autoclaved food and water ad libitum.
Copyright
© 2016, Fu et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Sam68/KHDRBS1-dependent NF-κB activation confers radioprotection to the colon epithelium in γ-irradiated mice
eLife 5:e21957.
https://doi.org/10.7554/eLife.21957
