title: p53 and PUMA independently regulate apoptosis of intestinal epithelial cells in patients and mice with colitis.
abstract: OBJECTIVE
  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.
authors.affiliation: Division of Gastroenterology, Department of Medicine Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Ramanarao
authors.initials: R
authors.lastname: Dirisina
authors.forename: Rebecca B
authors.initials: RB
authors.lastname: Katzman
authors.forename: Tatiana
authors.initials: T
authors.lastname: Goretsky
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Managlia
authors.forename: Navdha
authors.initials: N
authors.lastname: Mittal
authors.forename: David B
authors.initials: DB
authors.lastname: Williams
authors.forename: Wei
authors.initials: W
authors.lastname: Qiu
authors.forename: Jian
authors.initials: J
authors.lastname: Yu
authors.forename: Navdeep S
authors.initials: NS
authors.lastname: Chandel
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.forename: Terrence A
authors.initials: TA
authors.lastname: Barrett
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000502:physiology*; D016022:Case-Control Studies; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D003092:Colitis / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology*; D003106:Colon / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D016264:Dextran Sulfate / Q000009:adverse effects; D004195:Disease Models, Animal; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D013601:T-Lymphocytes / Q000473:pathology / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology*
chemical_list: D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; C488588:PUMA protein, mouse; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D016264:Dextran Sulfate; D053148:Caspase 3; D053453:Caspase 9