p53 and PUMA Independently Regulate Apoptosis of Intestinal Epithelial Cells in Patients and Mice With Colitis
| Autor: | Lin Zhang, Terrence A. Barrett, Rebecca B. Katzman, Jian Yu, Navdha Mittal, Tatiana Goretsky, Ramanarao Dirisina, David Williams, Wei Qiu, Elizabeth Managlia, Navdeep S. Chandel |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
Programmed cell death
Colon T-Lymphocytes Apoptosis Biology digestive system Article Mice Bcl-2-associated X protein Intestinal mucosa Proto-Oncogene Proteins hemic and lymphatic diseases Puma medicine Animals Humans Intestinal Mucosa Colitis Mice Knockout Hepatology Caspase 3 Tumor Suppressor Proteins Dextran Sulfate Intrinsic apoptosis Gastroenterology biology.organism_classification medicine.disease Molecular biology Caspase 9 digestive system diseases Mice Inbred C57BL Disease Models Animal Bcl-2 homologous antagonist killer Case-Control Studies Immunology biology.protein Tumor Suppressor Protein p53 biological phenomena cell phenomena and immunity Apoptosis Regulatory Proteins Signal Transduction |
| Zdroj: | Gastroenterology. 141:1036-1045 |
| ISSN: | 0016-5085 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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