title: IEX-1 deficiency protects against colonic cancer.
abstract: The immediate early response gene X-1 (IEX-1) is involved in regulation of various cellular processes including proliferation, apoptosis in part by controlling homeostasis of reactive oxygen species (ROS) at mitochondria. The present study shows reduced inflammatory responses and colorectal cancer in IEX-1 knockout (KO) mice treated with azoxymethane/dextran sulfate sodium (DSS). However, DSS induced worse colitis in RAG(-/-)IEX-1(-/-) double KO mice than in RAG and IEX-1 single KO mice, underscoring an importance of T cells in IEX-1 deficiency-induced protection against colon inflammation. Lack of IEX-1 promoted the differentiation of interleukin (IL)-17-producing T cells, concomitant with upregulation of Gαi2 expression, a gene that is well-documented for its role in the control of inflammation in the colon. In accordance with this, T-helper 17 (T(H)17) cell differentiation was compromised in the absence of Gαi2, and deletion of Gαi2 in T cells alone aggravated colon inflammation and colorectal cancer development after azoxymethane/DSS treatment. Null mutation of IEX-1 also enhanced both proliferation and apoptosis of intestinal epithelial cells (IEC) after injury. A potential impact of this altered IEC turnover on colon inflammation and cancer development is discussed. These observations provide a linkage of IEX-1 and Gαi2 expression in the regulation of T(H)17 cell differentiation and suggest a previously unappreciated role for IEX-1 in the control of colon epithelial homeostasis.
authors.affiliation: Wellman Center for Photomedicine, Department of Dermatology, Massachusetts General Hospital, and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Irina V
authors.initials: IV
authors.lastname: Ustyugova
authors.forename: Liang
authors.initials: L
authors.lastname: Zhi
authors.forename: Joel
authors.initials: J
authors.lastname: Abramowitz
authors.forename: Lutz
authors.initials: L
authors.lastname: Birnbaumer
authors.forename: Mei X
authors.initials: MX
authors.lastname: Wu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D001397:Azoxymethane / Q000633:toxicity; D049109:Cell Proliferation / Q000187:drug effects; D003092:Colitis / Q000139:chemically induced / Q000235:genetics / Q000276:immunology*; D003106:Colon / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D003110:Colonic Neoplasms / Q000235:genetics / Q000276:immunology*; D016207:Cytokines / Q000235:genetics; D016264:Dextran Sulfate / Q000633:toxicity; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005260:Female; D051960:GTP-Binding Protein alpha Subunit, Gi2 / Q000235:genetics / Q000276:immunology; D015870:Gene Expression / Q000187:drug effects; D017874:Immediate-Early Proteins / Q000235:genetics / Q000276:immunology*; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D058504:Th17 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
chemical_list: D016207:Cytokines; C518820:IEX-1 protein, mouse; D017874:Immediate-Early Proteins; D016264:Dextran Sulfate; D051960:GTP-Binding Protein alpha Subunit, Gi2; D001397:Azoxymethane