title: Jnk2 deletion disrupts intestinal mucosal homeostasis and maturation by differentially modulating RNA-binding proteins HuR and CUGBP1.
abstract: Homeostasis and maturation of the mammalian intestinal epithelium are preserved through strict regulation of cell proliferation, apoptosis, and differentiation, but the exact mechanism underlying this process remains largely unknown. c-Jun NH2-terminal kinase 2 (JNK2) is highly expressed in the intestinal mucosa, and its activation plays an important role in proliferation and also mediates apoptosis in cultured intestinal epithelial cells (IECs). Here, we investigated the in vivo function of JNK2 in the regulation of intestinal epithelial homeostasis and maturation by using a targeted gene deletion approach. Targeted deletion of the jnk2 gene increased cell proliferation within the crypts in the small intestine and disrupted mucosal maturation as indicated by decreases in the height of villi and the villus-to-crypt ratio. JNK2 deletion also decreased susceptibility of the intestinal epithelium to apoptosis. JNK2-deficient intestinal epithelium was associated with an increase in the level of the RNA-binding protein HuR and with a decrease in the abundance of CUG-binding protein 1 (CUGBP1). In studies in vitro, JNK2 silencing protected intestinal epithelial cell-6 (IEC-6) cells against apoptosis and this protection was prevented by inhibiting HuR. Ectopic overexpression of CUGBP1 repressed IEC-6 cell proliferation, whereas CUGBP1 silencing enhanced cell growth. These results indicate that JNK2 is essential for maintenance of normal intestinal epithelial homeostasis and maturation under biological conditions by differentially modulating HuR and CUGBP1.
authors.affiliation: Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland; Baltimore Veterans Affairs Medical Center, Baltimore, Maryland.
authors.forename: Hee Kyoung
authors.initials: HK
authors.lastname: Chung
authors.affiliation: Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland; Baltimore Veterans Affairs Medical Center, Baltimore, Maryland.
authors.forename: Jaladanki N
authors.initials: JN
authors.lastname: Rao
authors.affiliation: Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland; Baltimore Veterans Affairs Medical Center, Baltimore, Maryland.
authors.forename: Tongtong
authors.initials: T
authors.lastname: Zou
authors.affiliation: Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland; Baltimore Veterans Affairs Medical Center, Baltimore, Maryland.
authors.forename: Lan
authors.initials: L
authors.lastname: Liu
authors.affiliation: Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland; Baltimore Veterans Affairs Medical Center, Baltimore, Maryland.
authors.forename: Lan
authors.initials: L
authors.lastname: Xiao
authors.affiliation: Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, Maryland;
authors.forename: Hui
authors.initials: H
authors.lastname: Gu
authors.affiliation: Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland; Baltimore Veterans Affairs Medical Center, Baltimore, Maryland.
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Turner
authors.affiliation: Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, Maryland;
authors.forename: Peixin
authors.initials: P
authors.lastname: Yang
authors.affiliation: Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland; Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland; and Baltimore Veterans Affairs Medical Center, Baltimore, Maryland jwang@smail.umaryland.edu.
authors.forename: Jian-Ying
authors.initials: JY
authors.lastname: Wang
mesh_terms: D000818:Animals; D000067879:CELF1 Protein; D049109:Cell Proliferation; D002478:Cells, Cultured; D051959:ELAV Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics; D006706:Homeostasis / Q000235:genetics; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D048056:Mitogen-Activated Protein Kinase 9 / Q000235:genetics* / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000067879:CELF1 Protein; C502743:CELF1 protein, mouse; D051959:ELAV Proteins; D016601:RNA-Binding Proteins; D048056:Mitogen-Activated Protein Kinase 9
keywords: apoptosis; cell proliferation; mucosal growth; posttranscriptional regulation
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