title: Epithelial PIK3R1 (p85) and TP53 Regulate Survivin Expression during Adaptation to Ileocecal Resection.
abstract: Intestinal adaptation to small-bowel resection (SBR) after necrotizing enterocolitis expands absorptive surface areas and promotes enteral autonomy. Survivin increases proliferation and blunts apoptosis. The current study examines survivin in intestinal epithelial cells after ileocecal resection. Wild-type and epithelial Pik3r1 (p85α)-deficient mice underwent sham surgery or 30% resection. RNA and protein were isolated from small bowel to determine levels of β-catenin target gene expression, activated caspase-3, survivin, p85α, and Trp53. Healthy and post-resection human infant small-bowel sections were analyzed for survivin, Ki-67, and TP53 by immunohistochemistry. Five days after ileocecal resection, epithelial levels of survivin increased relative to sham-operated on mice, which correlated with reduced cleaved caspase-3, p85α, and Trp53. At baseline, p85α-deficient intestinal epithelial cells had less Trp53 and more survivin, and relative responses to resection were blunted compared with wild-type. In infant small bowel, survivin in transit amplifying cells increased 71% after SBR. Resection increased proliferation and decreased numbers of TP53-positive epithelial cells. Data suggest that ileocecal resection reduces p85α, which lowers TP53 activation and releases survivin promoter repression. The subsequent increase in survivin among transit amplifying cells promotes epithelial cell proliferation and lengthens crypts. These findings suggest that SBR reduces p85α and TP53, which increases survivin and intestinal epithelial cell expansion during therapeutic adaptation in patients with short bowel syndrome.
authors.affiliation: Department of Pediatrics, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois.
authors.forename: Valeria
authors.initials: V
authors.lastname: Cohran
authors.affiliation: Department of Pediatrics, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Managlia
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, University of Kentucky, Lexington, Kentucky.
authors.forename: Emily M
authors.initials: EM
authors.lastname: Bradford
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, University of Kentucky, Lexington, Kentucky.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Goretsky
authors.affiliation: Department of Surgery, Comprehensive Transplant Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Ting
authors.initials: T
authors.lastname: Li
authors.affiliation: Division of Gastroenterology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Rebecca B
authors.initials: RB
authors.lastname: Katzman
authors.affiliation: Division of Gastroenterology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Paul
authors.initials: P
authors.lastname: Cheresh
authors.affiliation: Department of Pediatrics, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois.
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Brown
authors.affiliation: Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hawkins
authors.affiliation: Department of Pediatrics, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois.
authors.forename: Shirley X L
authors.initials: SXL
authors.lastname: Liu
authors.affiliation: Department of Pediatrics, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois.
authors.forename: Isabelle G
authors.initials: IG
authors.lastname: De Plaen
authors.affiliation: Division of Neonatology, Department of Pediatrics, Vanderbilt University and Monroe Carell Jr. Children's Hospital, Nashville, Tennessee.
authors.forename: Jörn-Hendrik
authors.initials: JH
authors.lastname: Weitkamp
authors.affiliation: Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Michael
authors.initials: M
authors.lastname: Helmrath
authors.affiliation: Department of Surgery, Comprehensive Transplant Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, University of Kentucky, Lexington, Kentucky; Division of Gastroenterology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois. Electronic address: t.barrett@uky.edu.
authors.forename: Terrence A
authors.initials: TA
authors.lastname: Barrett
mesh_terms: D000222:Adaptation, Physiological / Q000502:physiology*; D000818:Animals; D015153:Blotting, Western; D058543:Class Ia Phosphatidylinositol 3-Kinase; D013505:Digestive System Surgical Procedures / Q000009:adverse effects; D004195:Disease Models, Animal; D020345:Enterocolitis, Necrotizing / Q000601:surgery; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D007231:Infant, Newborn; D051034:Inhibitor of Apoptosis Proteins / Q000096:biosynthesis / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D012097:Repressor Proteins / Q000096:biosynthesis; D012778:Short Bowel Syndrome / Q000209:etiology / Q000378:metabolism*; D000077022:Survivin; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D058543:Class Ia Phosphatidylinositol 3-Kinase; D016326:Extracellular Matrix Proteins; D051034:Inhibitor of Apoptosis Proteins; D019869:Phosphatidylinositol 3-Kinases; D012097:Repressor Proteins; D000077022:Survivin; D016159:Tumor Suppressor Protein p53; C107489:BIRC5 protein, human; C117749:Birc5 protein, mouse; C094556:Ecm1 protein, mouse; C588001:PIK3R1 protein, human