title: Loss of Survivin in Intestinal Epithelial Progenitor Cells Leads to Mitotic Catastrophe and Breakdown of Gut Immune Homeostasis.
abstract: A tightly regulated balance of proliferation and cell death of intestinal epithelial cells (IECs) is essential for maintenance of gut homeostasis. Survivin is highly expressed during embryogenesis and in several cancer types, but little is known about its role in adult gut tissue. Here, we show that Survivin is specifically expressed in transit-amplifying cells and Lgr5(+) stem cells. Genetic loss of Survivin in IECs resulted in destruction of intestinal integrity, mucosal inflammation, and death of the animals. Survivin deletion was associated with decreased epithelial proliferation due to defective chromosomal segregation. Moreover, Survivin-deficient animals showed induced phosphorylation of p53 and H2AX and increased levels of cell-intrinsic apoptosis in IECs. Consequently, induced deletion of Survivin in Lgr5(+) stem cells led to cell death. In summary, Survivin is a key regulator of gut tissue integrity by regulating epithelial homeostasis in the stem cell niche.
authors.affiliation: Department of Medicine 1, University Medical Center, Friedrich-Alexander-University, 91052 Erlangen, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Martini
authors.affiliation: Department of Medicine 1, University Medical Center, Friedrich-Alexander-University, 91052 Erlangen, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Wittkopf
authors.affiliation: Department of Medicine 1, University Medical Center, Friedrich-Alexander-University, 91052 Erlangen, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Günther
authors.affiliation: Department of Medicine 1, University Medical Center, Friedrich-Alexander-University, 91052 Erlangen, Germany.
authors.forename: Moritz
authors.initials: M
authors.lastname: Leppkes
authors.affiliation: Department of Biochemistry, Kindai University Faculty of Medicine, Osaka 589-8511, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Okada
authors.affiliation: Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich, Norfolk NR4 7TJ, UK.
authors.forename: Alastair J
authors.initials: AJ
authors.lastname: Watson
authors.affiliation: Department of Medicine 1, University Medical Center, Friedrich-Alexander-University, 91052 Erlangen, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Podstawa
authors.affiliation: Department of Medicine 1, University Medical Center, Friedrich-Alexander-University, 91052 Erlangen, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Backert
authors.affiliation: Department of Nephropathology, University Medical Center, Friedrich-Alexander-University, 91052 Erlangen, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Amann
authors.affiliation: Department of Medicine 1, University Medical Center, Friedrich-Alexander-University, 91052 Erlangen, Germany.
authors.forename: Markus F
authors.initials: MF
authors.lastname: Neurath
authors.affiliation: Department of Medicine 1, University Medical Center, Friedrich-Alexander-University, 91052 Erlangen, Germany. Electronic address: christoph.becker@uk-erlangen.de.
authors.forename: Christoph
authors.initials: C
authors.lastname: Becker
mesh_terms: D000818:Animals; D016923:Cell Death; D002455:Cell Division; D002470:Cell Survival; D004847:Epithelial Cells / Q000473:pathology*; D017353:Gene Deletion; D006706:Homeostasis; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000172:deficiency* / Q000378:metabolism; D007422:Intestines / Q000276:immunology* / Q000648:ultrastructure; D051379:Mice; D008938:Mitosis; D012097:Repressor Proteins / Q000172:deficiency* / Q000378:metabolism; D055153:Stem Cell Niche; D013234:Stem Cells / Q000473:pathology*; D000077022:Survivin
chemical_list: C107489:BIRC5 protein, human; C117749:Birc5 protein, mouse; D051034:Inhibitor of Apoptosis Proteins; D012097:Repressor Proteins; D000077022:Survivin