Nurr1 promotes intestinal regeneration after ischemia/reperfusion injury by inhibiting the expression of p21 (Waf1/Cip1)

作者：Zu, Guo; Yao, Jihong; Ji, Anlong; Ning, Shili; Luo, Fuwen; Li, Zhenlu; Feng, Dongcheng; Rui, Yiqi; Li, Yang; Wang, Guangzhi; Tian, Xiaofeng^*

来源：Journal of Molecular Medicine-JMM, 2017, 95(1): 83-95.

DOI：10.1007/s00109-016-1464-6

• Intestine
• ischemia/reperfusion
• Regeneration
• Nuclear receptor-related protein 1
• p21 (Wat1/Cip1)

Intestinal ischemia/reperfusion (I/R) injury is a potentially life-threatening condition that can cause injuries to remote organs at the end stage. The damage caused by intestinal 1/R insult induces changes in the barrier functions of the intestine, and the intrinsic mechanism of regeneration is often insufficient to restore barrier functions, as indicated by the high mortality rate of patients experiencing intestinal FR injury. However, little is known about the mechanisms of intestinal regeneration after 1/R injury. Here, we reported that nuclear receptor-related protein 1 (Nurrl), a nuclear orphan receptor, was induced during intestinal regeneration after I/R. Our findings showed that Nurrl expression was consistent with the expression of Ki-67 and phosphorylated histone H3 (pH 3) in the intestine after UR injury. Nurrl knockdown led to Glphase arrest mediated by p21 (Waf1/Cip1) activation, but Nurrl overexpression reduced the proportion of IEC-6 cells in G1 phase as a result of p21 inhibition in a p53-independent manner. Using chromatin immunoprecipitation assays, luciferase assays, and mutational analysis, we demonstrated that Nurrl directly inhibited the transcription of p21. These results define a novel NIBTI/p21 pathway that is involved in intestinal regeneration after PR injury. These findings provide novel molecular insights into the pathogenesis of intestinal regeneration after I/R and possibly support the development of new potential therapies for intestinal UR injury.

• 出版日期2017-1
• 单位大连医科大学