title: Pharmacologically blocking p53-dependent apoptosis protects intestinal stem cells and mice from radiation.
abstract: Exposure to high levels of ionizing radiation (IR) leads to debilitating and dose-limiting gastrointestinal (GI) toxicity. Using three-dimensional mouse crypt culture, we demonstrated that p53 target PUMA mediates radiation-induced apoptosis via a cell-intrinsic mechanism, and identified the GSK-3 inhibitor CHIR99021 as a potent radioprotector. CHIR99021 treatment improved Lgr5+ cell survival and crypt regeneration after radiation in culture and mice. CHIR99021 treatment specifically blocked apoptosis and PUMA induction and K120 acetylation of p53 mediated by acetyl-transferase Tip60, while it had no effect on p53 stabilization, phosphorylation or p21 induction. CHIR99021 also protected human intestinal cultures from radiation by PUMA but not p21 suppression. These results demonstrate that p53 posttranslational modifications play a key role in the pathological and apoptotic response of the intestinal stem cells to radiation and can be targeted pharmacologically.
authors: Department of Pathology, University of Pittsburgh School of Medicine, 5117 Centre Avenue, Pittsburgh, PA 15213.|University of Pittsburgh Cancer Institute, 5117 Centre Avenue, Pittsburgh, PA 15213.
authors: Xinwei
authors: X
authors: Wang
authors: Department of Pathology, University of Pittsburgh School of Medicine, 5117 Centre Avenue, Pittsburgh, PA 15213.|University of Pittsburgh Cancer Institute, 5117 Centre Avenue, Pittsburgh, PA 15213.
authors: Liang
authors: L
authors: Wei
authors: Department of Pathology, University of Pittsburgh School of Medicine, 5117 Centre Avenue, Pittsburgh, PA 15213.
authors: Julie M
authors: JM
authors: Cramer
authors: Department of Pathology, University of Pittsburgh School of Medicine, 5117 Centre Avenue, Pittsburgh, PA 15213.|University of Pittsburgh Cancer Institute, 5117 Centre Avenue, Pittsburgh, PA 15213.
authors: Brian J
authors: BJ
authors: Leibowitz
authors: Department of Pathology, University of Pittsburgh School of Medicine, 5117 Centre Avenue, Pittsburgh, PA 15213.|University of Pittsburgh Cancer Institute, 5117 Centre Avenue, Pittsburgh, PA 15213.
authors: Colleen
authors: C
authors: Judge
authors: University of Pittsburgh Cancer Institute, 5117 Centre Avenue, Pittsburgh, PA 15213.|Department of Radiation Oncology, University of Pittsburgh School of Medicine, 5117 Centre Avenue, Pittsburgh, PA 15213.
authors: Michael
authors: M
authors: Epperly
authors: University of Pittsburgh Cancer Institute, 5117 Centre Avenue, Pittsburgh, PA 15213.|Department of Radiation Oncology, University of Pittsburgh School of Medicine, 5117 Centre Avenue, Pittsburgh, PA 15213.
authors: Joel
authors: J
authors: Greenberger
authors: Department of Pathology, University of Kansas Medical Center, Stowers Institute for Medical Research, 1000 E 50th Street, Kansas City, MS 64110.
authors: Fengchao
authors: F
authors: Wang
authors: Department of Pathology, University of Kansas Medical Center, Stowers Institute for Medical Research, 1000 E 50th Street, Kansas City, MS 64110.
authors: Linheng
authors: L
authors: Li
authors: Department of Surgery, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA 90073.
authors: Matthias G
authors: MG
authors: Stelzner
authors: Departments of Surgery and Pediatrics, David Geffen School of Medicine, University of California, 10833 Le Conte Ave, Los Angeles, CA 90095.
authors: James C Y
authors: JCY
authors: Dunn
authors: Departments of Surgery and Pediatrics, David Geffen School of Medicine, University of California, 10833 Le Conte Ave, Los Angeles, CA 90095.
authors: Martin G
authors: MG
authors: Martin
authors: Department of Pathology, University of Pittsburgh School of Medicine, 5117 Centre Avenue, Pittsburgh, PA 15213.
authors: Eric
authors: E
authors: Lagasse
authors: University of Pittsburgh Cancer Institute, 5117 Centre Avenue, Pittsburgh, PA 15213.|Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, 5117 Centre Avenue, Pittsburgh, PA 15213.
authors: Lin
authors: L
authors: Zhang
authors: Department of Pathology, University of Pittsburgh School of Medicine, 5117 Centre Avenue, Pittsburgh, PA 15213.|University of Pittsburgh Cancer Institute, 5117 Centre Avenue, Pittsburgh, PA 15213.|Department of Radiation Oncology, University of Pittsburgh School of Medicine, 5117 Centre Avenue, Pittsburgh, PA 15213.
authors: Jian
authors: J
authors: Yu
mesh_terms: D000107:Acetylation; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency / Q000235:genetics; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005767:Gastrointestinal Diseases / Q000209:etiology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000528:radiation effects; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors; D006801:Humans; D007422:Intestines / Q000166:cytology*; D051379:Mice; D018345:Mice, Knockout; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011833:Radiation Injuries, Experimental; D011836:Radiation Tolerance / Q000187:drug effects / Q000235:genetics; D011839:Radiation, Ionizing; D011837:Radiation-Protective Agents / Q000494:pharmacology*; D011878:Radiotherapy / Q000009:adverse effects; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D013234:Stem Cells / Q000187:drug effects* / Q000378:metabolism* / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics
chemical_list: D051017:Apoptosis Regulatory Proteins; C473711:Chir 99021; C493597:Lgr5 protein, mouse; C488588:PUMA protein, mouse; D011725:Pyridines; D011743:Pyrimidines; D011837:Radiation-Protective Agents; D043562:Receptors, G-Protein-Coupled; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D038362:Glycogen Synthase Kinase 3