title: BCL-2 modifying factor (BMF) is a central regulator of anoikis in human intestinal epithelial cells.
abstract: BCL-2 modifying factor (BMF) is a sentinel considered to register damage at the cytoskeleton and to convey a death signal to B-cell lymphoma 2. B-cell lymphoma 2 is neutralized by BMF and thereby facilitates cytochrome C release from mitochondria. We investigated the role of BMF for intestinal epithelial cell (IEC) homeostasis. Acute colitis was induced in Bmf-deficient mice (Bmf(-/-)) with dextran sulfate sodium. Colonic crypt length in Bmf(-/-) mice was significantly increased as compared with WT mice. Dextran sulfate sodium induced less signs of colitis in Bmf(-/-) mice, as weight loss was reduced compared with the WT. Primary human IEC exhibited increased BMF in the extrusion zone. Quantitative PCR showed a significant up-regulation of BMF expression after initiation of anoikis in primary human IEC. BMF was found on mitochondria during anoikis, as demonstrated by Western blot analysis. RNAi mediated knockdown of BMF reduced the number of apoptotic cells and led to reduced caspase 3 activity. A significant increase in phospho-AKT was determined after RNAi treatment. BMF knockdown supports survival of IEC. BMF is induced in human IEC by the loss of cell attachment and is likely to play an important role in the regulation of IEC survival.
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, University Hospital of Zürich, 8091 Zürich, Switzerland. martin.hausmann@usz.ch
authors.forename: Martin
authors.initials: M
authors.lastname: Hausmann
authors.forename: Katharina
authors.initials: K
authors.lastname: Leucht
authors.forename: Christian
authors.initials: C
authors.lastname: Ploner
authors.forename: Stephan
authors.initials: S
authors.lastname: Kiessling
authors.forename: Andreas
authors.initials: A
authors.lastname: Villunger
authors.forename: Helen
authors.initials: H
authors.lastname: Becker
authors.forename: Claudia
authors.initials: C
authors.lastname: Hofmann
authors.forename: Werner
authors.initials: W
authors.lastname: Falk
authors.forename: Michaela
authors.initials: M
authors.lastname: Krebs
authors.forename: Silvia
authors.initials: S
authors.lastname: Kellermeier
authors.forename: Michael
authors.initials: M
authors.lastname: Fried
authors.forename: Jürgen
authors.initials: J
authors.lastname: Schölmerich
authors.forename: Florian
authors.initials: F
authors.lastname: Obermeier
authors.forename: Gerhard
authors.initials: G
authors.lastname: Rogler
mesh_terms: D000208:Acute Disease; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D023102:Anoikis / Q000502:physiology*; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D003092:Colitis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D016264:Dextran Sulfate / Q000633:toxicity; D004847:Epithelial Cells / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C486655:BMF protein, human; C435486:Bmf protein, mouse; D016264:Dextran Sulfate; D051057:Proto-Oncogene Proteins c-akt; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3