p21 protects "Super p53" mice from the radiation-induced gastrointestinal syndrome.
ABSTRACT Exposure of the gastrointestinal (GI) tract to high doses of radiation can lead to lethality from the GI syndrome. Although the molecular mechanism regulating the GI syndrome remains to be fully defined, we have recently demonstrated that p53 within the GI epithelial cells controls the radiation-induced GI syndrome. Mice lacking p53 in the GI epithelium were sensitized to the GI syndrome, while transgenic mice with one additional copy of p53 called "Super p53" mice were protected from the GI syndrome. Here, we crossed Super p53 mice to p21⁻/⁻ mice that lack the cyclin-dependent kinase inhibitor p21. Super p53; p21⁻/⁻ mice were sensitized to the GI syndrome compared to Super p53 mice that retain one p21 allele. In addition, mice lacking p21 were not protected from the GI syndrome with one extra copy of p53. These results suggest that p21 protects Super p53 mice from the GI syndrome.
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ABSTRACT: SIRT1 regulates the DNA damage response by deacetylating p53, thereby repressing p53 transcriptional output. Here, we demonstrate that the sorting protein PACS-2 regulates SIRT1-mediated deacetylation of p53 to modulate the DNA damage response. PACS-2 knockdown cells failed to efficiently undergo p53-induced cell-cycle arrest in response to DNA damage. Accordingly, p53 acetylation was reduced both in PACS-2 knockdown cells and thymocytes from Pacs-2(-/-) mice, thereby blunting induction of the cyclin-dependent kinase inhibitor p21 (CDKN1A). The SIRT1 inhibitor EX-527 or SIRT1 knockdown restored p53 acetylation and p21 induction as well as p21-dependent cell-cycle arrest in PACS-2 knockdown cells. Trafficking studies revealed that cytoplasmic PACS-2 shuttled to the nucleus, where it interacted with SIRT1 and repressed SIRT1-mediated p53 deacetylation. Correspondingly, in vitro assays demonstrated that PACS-2 directly inhibited SIRT1-catalyzed p53 deacetylation. Together, these findings identify PACS-2 as an in vivo mediator of the SIRT1-p53-p21 axis that modulates the DNA damage response.Cell Reports 08/2014; · 7.21 Impact Factor
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ABSTRACT: The role of bone marrow (BM) and BM-derived cells in radiation-induced acute gastrointestinal (GI) syndrome is controversial. Here we use bone marrow transplantation (BMT), total body irradiation (TBI) and abdominal irradiation (ABI) models to demonstrate a very limited, if any, role of BM-derived cells in acute GI injury and recovery. Compared with WT BM recipients, mice receiving BM from radiation-resistant PUMA KO mice show no protection from crypt and villus injury or recovery after 15 or 12 Gy TBI, but have a significant survival benefit at 12 Gy TBI. PUMA KO BM significantly protects donor-derived pan-intestinal haematopoietic (CD45+) and endothelial (CD105+) cells after IR. We further show that PUMA KO BM fails to enhance animal survival or crypt regeneration in radiosensitive p21 KO-recipient mice. These findings clearly separate the effects of radiation on the intestinal epithelium from those on the BM and endothelial cells in dose-dependent acute radiation toxicity.Nature Communications 03/2014; 5:3494. · 10.74 Impact Factor
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ABSTRACT: Radiation and chemotherapy remain the most effective and widely used cancer treatments. These treatments cause DNA damage and selectively target rapidly proliferating cells such as cancer cells, as well as inevitably cause damage to normal tissues, particularly those undergoing rapid self renewal. The side effects associated with radiation and chemotherapy are most pronounced in the hematopoietic (HP) system and gastrointestinal (GI) tract. These tissues are fast renewing and have a well-defined stem cell compartment that plays an essential role in homeostasis, and in treatment-induced acute injury that is dose limiting. Using recently defined intestinal stem cell markers and mouse models, a great deal of insight has been gained in the biology of intestinal stem cells (ISCs), which will undoubtedly help further mechanistic understanding of their injury. This review will cover historic discoveries and recent advances in the identification and characterization of intestinal stem cells, their responses to genotoxic stress, and a new crypt and intestinal stem cell culture system. The discussion will include key pathways regulating intestinal crypt and stem cell injury and regeneration caused by cancer treatments, and strategies for their protection. The focus will be on the acute phase of cell killing in mouse radiation models, where our understanding of the mechanisms in relation to intestinal stem cells is most advanced and interventions appear most effective.Translational Cancer Research 10/2013; 2(5):384-396.