Epithelial PIK3R1 (p85) and TP53 Regulate Survivin Expression during Adaptation to Ileocecal Resection

Valeria Cohran, Elizabeth Managlia, Emily M. Bradford, Tatiana Goretsky, Ting Li, Rebecca B. Katzman, Paul Cheresh, Jeffrey B. Brown, Jennifer Hawkins, Shirley X.L. Liu, Isabelle G. De Plaen, Jörn Hendrik Weitkamp, Michael Helmrath, Zheng Zhang, Terrence A. Barrett

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

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.

Original languageEnglish
Pages (from-to)1837-1846
Number of pages10
JournalAmerican Journal of Pathology
Volume186
Issue number7
DOIs
StatePublished - Jul 2016

Bibliographical note

Funding Information:
Supported by NIH grants R01DK-054778 and R01AI-6171702 (T.A.B.), the Eunice Kennedy Shriver National Institute of Child Health and Human Development grant K08HD061607 (J.-H.W.), and the Vanderbilt University Medical Center's Digestive Disease Research Center, supported by NIH grants P30DK058404 , R01 HD060876 (I.G.D.P.), K12 HD052902 (V.C.), and DK066161 (J.B.B.). E.M.B. was supported by T32-CA080621 (Richard Carthew, PI). Mouse surgeries were supported by the Microsurgery Core of the Comprehensive Transplant Center at Northwestern University .

Publisher Copyright:
© 2016 American Society for Investigative Pathology

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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