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: In the human gastrointestinal tract, the functional mucosa of the small intestine has the highest capacity for absorption of nutrients and rapid proliferation rates, making it vulnerable to chemoradiotherapy. Recent understanding of the protective role of p53-mediated cell cycle arrest in the small intestinal mucosa has led researchers to explore new avenues to mitigate mucosal injury during cancer treatment. A traditional p53 inhibitor and two other molecules that exhibit strong protective effects on normal small intestinal epithelium during anticancer drug treatment and radiation therapy are introduced in this work. The objective of this review was to update current knowledge regarding potential mechanisms and targets that inhibit the side effects induced by chemoradiotherapy.Cancer Biology and Medicine 03/2012; 9(1):1-8. DOI:10.3969/j.issn.2095-3941.2012.01.001
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ABSTRACT: Radiation exposure leads to diverse outcomes in vivo across different tissues and even within the same cell lineage. The diversity of radiation response in vivo is at least partially attributable to the status of the tumor suppressor p53, a master regulator of cellular response to stress, and activation of its transcriptional targets. In certain cells, such as hematopoietic progenitors and transit amplifying cells in the gastrointestinal epithelium, activation of p53 by radiation triggers the intrinsic pathway of apoptosis. However, in many other cells, activation of p53 by radiation does not result in apoptosis, which underscores the importance of understanding the role of p53 in regulating radiation response through alternative mechanisms. In this review, we summarize recent studies using genetically engineered mice to dissect the role of p53 in 1) cells where its activation is dissociated from the intrinsic pathway of apoptosis, such as hematopoietic stem cells and vascular endothelial cells and 2) tissues where activation of the intrinsic pathway of apoptosis does not promote the acute radiation syndrome, such as the gastrointestinal epithelium. We highlight findings showing that the apoptosis-independent response of p53 to radiation in vivo can contribute to death or survival in a cell-type dependent manner, which underscores the complexity by which p53 regulates the cellular and tissue response to radiation.Translational Cancer Research 10/2013; 2(5):412-421.
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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.