title: ER stress transcription factor Xbp1 suppresses intestinal tumorigenesis and directs intestinal stem cells.
abstract: Unresolved endoplasmic reticulum (ER) stress in the epithelium can provoke intestinal inflammation. Hypomorphic variants of ER stress response mediators, such as X-box-binding protein 1 (XBP1), confer genetic risk for inflammatory bowel disease. We report here that hypomorphic Xbp1 function instructs a multilayered regenerative response in the intestinal epithelium. This is characterized by intestinal stem cell (ISC) expansion as shown by an inositol-requiring enzyme 1α (Ire1α)-mediated increase in Lgr5(+) and Olfm4(+) ISCs and a Stat3-dependent increase in the proliferative output of transit-amplifying cells. These consequences of hypomorphic Xbp1 function are associated with an increased propensity to develop colitis-associated and spontaneous adenomatous polyposis coli (APC)-related tumors of the intestinal epithelium, which in the latter case is shown to be dependent on Ire1α. This study reveals an unexpected role for Xbp1 in suppressing tumor formation through restraint of a pathway that involves an Ire1α- and Stat3-mediated regenerative response of the epithelium as a consequence of ER stress. As such, Xbp1 in the intestinal epithelium not only regulates local inflammation but at the same time also determines the propensity of the epithelium to develop tumors.
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge CB2 0QQ, England, UK.
authors.forename: Lukas
authors.initials: L
authors.lastname: Niederreiter
authors.forename: Teresa M J
authors.initials: TM
authors.lastname: Fritz
authors.forename: Timon E
authors.initials: TE
authors.lastname: Adolph
authors.forename: Anna-Maria
authors.initials: AM
authors.lastname: Krismer
authors.forename: Felix A
authors.initials: FA
authors.lastname: Offner
authors.forename: Markus
authors.initials: M
authors.lastname: Tschurtschenthaler
authors.forename: Magdalena B
authors.initials: MB
authors.lastname: Flak
authors.forename: Shuhei
authors.initials: S
authors.lastname: Hosomi
authors.forename: Michal F
authors.initials: MF
authors.lastname: Tomczak
authors.forename: Nicole C
authors.initials: NC
authors.lastname: Kaneider
authors.forename: Edina
authors.initials: E
authors.lastname: Sarcevic
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Kempster
authors.forename: Tim
authors.initials: T
authors.lastname: Raine
authors.forename: Daniela
authors.initials: D
authors.lastname: Esser
authors.forename: Philip
authors.initials: P
authors.lastname: Rosenstiel
authors.forename: Kenji
authors.initials: K
authors.lastname: Kohno
authors.forename: Takao
authors.initials: T
authors.lastname: Iwawaki
authors.forename: Herbert
authors.initials: H
authors.lastname: Tilg
authors.forename: Richard S
authors.initials: RS
authors.lastname: Blumberg
authors.forename: Arthur
authors.initials: A
authors.lastname: Kaser
mesh_terms: D000818:Animals; D019898:Autocrine Communication / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress; D004722:Endoribonucleases / Q000378:metabolism; D004789:Enzyme Activation; D017353:Gene Deletion; D017491:Genes, APC; D017370:Interleukin-11 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000473:pathology; D007422:Intestines / Q000473:pathology*; D053613:Janus Kinase 1 / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000071701:Regulatory Factor X Transcription Factors; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism* / Q000473:pathology*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D047368:Tumor Burden / Q000235:genetics; D000071717:X-Box Binding Protein 1
chemical_list: D004268:DNA-Binding Proteins; D017370:Interleukin-11; D015850:Interleukin-6; D016328:NF-kappa B; D000071701:Regulatory Factor X Transcription Factors; D050796:STAT3 Transcription Factor; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605544:Xbp1 protein, mouse; D053613:Janus Kinase 1; C510185:Ern1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D048670:MAP Kinase Kinase 4; D004722:Endoribonucleases
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