P53 and PUMA independently regulate apoptosis of intestinal epithelial cells in patients and mice with colitis

Ramanarao Dirisina, Rebecca B. Katzman, Tatiana Goretsky, Elizabeth Managlia, Navdha Mittal, David B. Williams, Wei Qiu, Jian Yu, Navdeep S. Chandel, Lin Zhang, Terrence A. Barrett*

*Corresponding author for this work

Research output: Contribution to journalArticle

48 Scopus citations

Abstract

Background & Aims: Inflammatory bowel disease (IBD) is associated with increased apoptosis of intestinal epithelial cells (IECs). Mutations in the tumor suppressor p53 appear during early stages of progression from colitis to cancer. We investigated the role of p53 and its target, p53-upregulated modulator of apoptosis (PUMA), in inflammation-induced apoptosis of IECs. Methods: Apoptosis was induced in mouse models of mucosal inflammation. Responses of IECs to acute, T-cell activation were assessed in wild-type, p53-/-, Bid-/-, Bim-/-, Bax3-/-, Bak-/-, PUMA-/-, and Noxa-/- mice. Responses of IECs to acute and chronic colitis were measured in mice following 1 or 3 cycles of dextran sulfate sodium (DSS), respectively. Apoptosis was assessed by TUNEL staining and measuring activity of caspases 3 and 9; levels of p53 and PUMA were assessed in colon tissue from patients with and without ulcerative colitis. Results: Apoptosis of IECs occurred in the lower crypts of colitic tissue from humans and mice. Colitis induction with anti-CD3 or 3 cycles of DSS increased apoptosis and protein levels of p53 and PUMA in colonic crypt IECs. In p53 -/- and PUMA-/- mice, apoptosis of IECs was significantly reduced but inflammation was not. Levels of p53 and PUMA were increased in inflamed mucosal tissues of mice with colitis and in patients with UC, compared with controls. Induction of PUMA in IECs of p53-/- mice indicated that PUMA-mediated apoptosis was independent of p53. Conclusions: In mice and humans, colon inflammation induces apoptosis of IECs via p53-dependent and -independent mechanisms; PUMA also activates an intrinsic apoptosis pathway associated with colitis.

Original languageEnglish (US)
Pages (from-to)1036-1045
Number of pages10
JournalGastroenterology
Volume141
Issue number3
DOIs
StatePublished - Sep 2011

Keywords

  • Cell Death
  • Crohn's Disease
  • IBD
  • Signaling
  • UC

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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    Dirisina, R., Katzman, R. B., Goretsky, T., Managlia, E., Mittal, N., Williams, D. B., Qiu, W., Yu, J., Chandel, N. S., Zhang, L., & Barrett, T. A. (2011). P53 and PUMA independently regulate apoptosis of intestinal epithelial cells in patients and mice with colitis. Gastroenterology, 141(3), 1036-1045. https://doi.org/10.1053/j.gastro.2011.05.032