Disruption of Sag/Rbx2/Roc2 induces radiosensitization by increasing ROS levels and blocking NF-kappaB activation in mouse embryonic stem cells.

Free Radical Biology & Medicine
M TanYi Sun

Abstract

SAG (sensitive to apoptosis gene; also known as RBX2 or ROC2) is a dual-function protein with antioxidant activity when acting alone or E3 ligase activity when complexed with other components of SCF (Skp1, cullins, F-box proteins) E3 ubiquitin ligases. SAG acts as a survival protein to inhibit apoptosis induced by a variety of stresses. Our recent work showed that SAG siRNA silencing sensitized cancer cells to radiation but the mechanism responsible remains elusive. Here we report that complete elimination of Sag expression via a gene-trapping strategy significantly sensitized mouse embryonic stem (ES) cells to radiation, with a sensitizing enhancement rate of 1.5-1.6. Radiosensitization was associated with increased steady-state levels of intracellular ROS (including superoxide) 24h after irradiation as well as enhancement of radiation-induced apoptosis. Furthermore, Sag elimination abrogated IkappaBalpha degradation leading to inhibition of NF-kappaB activation. Further detailed analysis revealed that IkappaBalpha is a direct substrate of SAG-SCF(beta-TrCP) E3 ubiquitin ligase. Taken together, these results support the hypothesis that Sag elimination via gene disruption sensitizes ES cells to radiation-induced cell killing by...Continue Reading

Citations

Jan 17, 2014·The Journal of Clinical Investigation·Hua LiYi Sun
Jul 16, 2014·Medical Oncology·Mei-juan ZhouHan-chun Chen
Mar 26, 2013·Journal of Genetics and Genomics = Yi Chuan Xue Bao·Chuan-Ming XieYi Sun
Aug 21, 2016·The American Journal of Pathology·Nathan D MathewsonPavan Reddy
Nov 30, 2019·Reproductive Biology and Endocrinology : RB&E·Jiayan XieGuang Wang
Mar 19, 2021·Cell & Bioscience·Qiyin ZhouYi Sun

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