title: Nurr1 promotes intestinal regeneration after ischemia/reperfusion injury by inhibiting the expression of p21 (Waf1/Cip1).
abstract: 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 I/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 I/R injury. However, little is known about the mechanisms of intestinal regeneration after I/R injury. Here, we reported that nuclear receptor-related protein 1 (Nurr1), a nuclear orphan receptor, was induced during intestinal regeneration after I/R. Our findings showed that Nurr1 expression was consistent with the expression of Ki-67 and phosphorylated histone H3 (pH 3) in the intestine after I/R injury. Nurr1 knockdown led to G1-phase arrest mediated by p21 (Waf1/Cip1) activation, but Nurr1 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 Nurr1 directly inhibited the transcription of p21. These results define a novel Nurr1/p21 pathway that is involved in intestinal regeneration after I/R 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 I/R injury.
  
  
  
  Nurr1 was induced during intestinal regeneration after I/R injury. Nurr1 promoted proliferation of intestinal epithelial cells after H/R injury. Nurr1 inhibited p21 expression in a p53-independent manner. Nurr1 inhibited p21 gene transcription by binding to p21 promoter directly.
authors.affiliation: Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, 116023, China.
authors.forename: Guo
authors.initials: G
authors.lastname: Zu
authors.affiliation: Department of Pharmacology, Dalian Medical University, Dalian, 116044, China.
authors.forename: Jihong
authors.initials: J
authors.lastname: Yao
authors.affiliation: Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, 116023, China.
authors.forename: Anlong
authors.initials: A
authors.lastname: Ji
authors.affiliation: Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, 116023, China.
authors.forename: Shili
authors.initials: S
authors.lastname: Ning
authors.affiliation: Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, 116023, China.
authors.forename: Fuwen
authors.initials: F
authors.lastname: Luo
authors.affiliation: Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, 116023, China.
authors.forename: Zhenlu
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, 116023, China.
authors.forename: Dongcheng
authors.initials: D
authors.lastname: Feng
authors.affiliation: Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, 116023, China.
authors.forename: Yiqi
authors.initials: Y
authors.lastname: Rui
authors.affiliation: Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, 116023, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, 116023, China.
authors.forename: Guangzhi
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, 116023, China. txfdl@dmu.edu.cn.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Tian
mesh_terms: D000818:Animals; D059447:Cell Cycle Checkpoints / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D015870:Gene Expression; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006801:Humans; D007422:Intestines / Q000502:physiology*; D008297:Male; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2 / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D012038:Regeneration / Q000235:genetics; D015427:Reperfusion Injury / Q000235:genetics* / Q000378:metabolism*; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; C539882:NR4A2 protein, human; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53
keywords: Intestine; Ischemia/reperfusion; Nuclear receptor-related protein 1; Regeneration; p21 (Waf1/Cip1)