Transient enhancement of p53 activity protects from radiation-induced gastrointestinal toxicity

Pant, Vinod; Xiong, Shunbin; Larsson, Connie A.; Aryal, Neeraj K.; Chau, Gilda; Tailor, Ramesh; Lozano, Guillermina

doi:10.1073/pnas.1909550116

Cited by 22 publications

(25 citation statements)

References 40 publications

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“…In summary, our results provide novel insight into a long-standing question in radiation biology: how does the tumor suppressor p53 suppress the development of the radiation-induced GI syndrome? 8,[20][21][22] Our results indicate that transient activation of p53 after irradiation is necessary to promote the emergence of revSCs. We demonstrate that Clu+ revSCs contribute to a significant fraction of regenerating epithelial crypts during the radiation-induced GI syndrome and the revSCs have also been previously shown to increase animal survival following gut damage 5 .…”

Section: Main Textmentioning

confidence: 62%

p53 promotes revival stem cells in the regenerating intestine after severe radiation injury

Morral

Ayyaz

Kuo

et al. 2023

Preprint

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Ionizing radiation induces cell death in the gastrointestinal (GI) epithelium by activating p53. However, p53 also prevents animal lethality caused by radiation-induced GI injury. Through single-cell RNA-sequencing of the irradiated mouse intestine, we find that p53 target genes are specifically enriched in stem cells of the regenerating epithelium, including revival stem cells that promote animal survival after GI damage. Accordingly, in mice with p53 deleted specifically in the GI epithelium, ionizing radiation fails to induce revival stem cells. Using intestinal organoids, we show that transient p53 expression is required for the induction of revival stem cells that is controlled by an Mdm2-mediated negative feedback loop. These results suggest that p53 suppresses severe radiation-indued GI injury by promoting intestinal epithelial cell reprogramming.

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Section: Main Textmentioning

confidence: 62%

p53 promotes revival stem cells in the regenerating intestine after severe radiation injury

Morral

Ayyaz

Kuo

et al. 2023

Preprint

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“…We previously reported 5-chloro-8-quinolinol as a modulator of p53 transactivation that effectively inhibits the GI syndrome through the induction of p21. Others demonstrated similar results by using RG7112, a chemical compound that activates p53-p21 pathway through the inhibition of p53-Mdm2 interaction [26]. Considering the fact that isorhamnetin moderately inhibited p53-p21 pathway in irradiated MOLT-4 cells, it would exert the suppressive effect against GI death independent of p53.…”

Section: Discussionmentioning

confidence: 70%

Isorhamnetin Promotes 53BP1 Recruitment through the Enhancement of ATM Phosphorylation and Protects Mice from Radiation Gastrointestinal Syndrome

Nishiyama

Morita

Tatsuta

et al. 2021

Genes

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Flavonoids are a subclass of polyphenols which are attractive, due to possessing various physiological activities, including a radioprotective effect. Tumor suppressor p53 is a primary regulator in the radiation response and is involved in the pathogenesis of radiation injuries. In this study, we revealed that isorhamnetin inhibited radiation cell death, and investigated its action mechanism focusing on DNA damage response. Although isorhamnetin moderated p53 activity, it promoted phosphorylation of ataxia telangiectasia mutated (ATM) and enhanced 53BP1 recruitment in irradiated cells. The radioprotective effect of isorhamnetin was not observed in the presence of ATM inhibitor, indicating that its protective effect was dependent on ATM. Furthermore, isorhamnetin-treated mice survived gastrointestinal death caused by a lethal dose of abdominal irradiation. These findings suggested that isorhamnetin enhances the ATM-dependent DNA repair process, which is presumably associated with the suppressive effect against GI syndrome.

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“…Similarly, previous studies found a significant decrease in p53 expression at 8 Gy radiation dose, supporting the present investigation [ 41 ]. Pretreatment with L-NAT to irradiated Neuro2a cells led to enhanced p53 expression as compared to irradiated cells (1.29 fold; p <0.05; Figures 11(c) , 11(f) and 11(g) ), further justified a prominent role of p53 in DNA repair and cell cycle arrest, which provides crucial time for the activation of various DNA-repair systems [ 46 , 47 ]. Pretreatment with L-NAT to irradiated Neuro2a cells showed a significant reduction in DNA damage compared to irradiated cells in the comet assay and a decrease in γ -H2aX protein expression that may correlate with an increase in p53 activity ( Figure 5(b) and 11(b) – 11(c) ).…”

Section: Discussionmentioning

confidence: 97%

Amelioration of Radiation-Induced Cell Death in Neuro2a Cells by Neutralizing Oxidative Stress and Reducing Mitochondrial Dysfunction Using N-Acetyl-L-Tryptophan

Kumar

Kumari

Pandey

et al. 2022

Oxidative Medicine and Cellular Longevity

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The deleterious effects of ionizing radiation on the central nervous system (CNS) are poorly understood. Radiation exposure during an accidental nuclear explosion, nuclear war, or radiotherapy causes severe brain damage. As a result, the current work is carried out to assess the radioprotective potential of N-acetyl-L-tryptophan (L-NAT) in neuronal cells. Radiation-induced cell death and its amelioration by L-NAT pretreatment were investigated using MTT, SRB, CFU, and comet assays. Flow cytometric and microscopic fluorescence assays were used to investigate radiation-induced oxidative stress, alteration in mitochondrial redox, Ca2+ homeostasis, depolarization of mitochondrial membrane potential, and its prevention with L-NAT pretreatment. Western blot analysis of Caspase-3, γ-H2aX, p53, ERK-1/2, and p-ERK-1/2 expression was carried out to identify the effects of L-NAT pretreatment on radiation-induced apoptosis and its regulatory proteins expression. The study demonstrated (MTT, SRB, and CFU assay) significant (~80%; p <0.001%) radioprotection in irradiated (LD50 IR dose) Neuro2a cells that were pretreated with L-NAT. In comparison to irradiated cells, L-NAT pretreatment resulted in significant (p <0.001%) DNA protection. A subsequent study revealed that L-NAT pretreatment of irradiated Neuro2a cells establishes oxidative stress by increasing antioxidant enzymes and mitochondrial redox homeostasis by inhibiting Ca2+ migration from the cytoplasm to the mitochondrial matrix and thus protects the mitochondrial membrane hyperpolarization. Caspase-3 and γ-H2aX protein expression decreased, while p-ERK1/2 and p53 expression increased in L-NAT pretreated irradiated cells compared to irradiated cells. Hence, L-NAT could be a potential radioprotective that may inhibit oxidative stress and DNA damage and maintain mitochondrial health and Ca2+ levels by activating p-ERK1/2 and p53 expression in Neuronal cells.

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Transient enhancement of p53 activity protects from radiation-induced gastrointestinal toxicity

Cited by 22 publications

References 40 publications

p53 promotes revival stem cells in the regenerating intestine after severe radiation injury

p53 promotes revival stem cells in the regenerating intestine after severe radiation injury

Isorhamnetin Promotes 53BP1 Recruitment through the Enhancement of ATM Phosphorylation and Protects Mice from Radiation Gastrointestinal Syndrome

Amelioration of Radiation-Induced Cell Death in Neuro2a Cells by Neutralizing Oxidative Stress and Reducing Mitochondrial Dysfunction Using N-Acetyl-L-Tryptophan

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