Rapamycin prevents strong phosphorylation of p53 on serine 46 and attenuates activation of the p53 pathway in A549 lung cancer cells exposed to actinomycin D

Krześniak, Małgorzata; Zajkowicz, Artur; Matuszczyk, Iwona; Rusin, Marek

doi:10.1016/j.mad.2014.06.002

Cited by 20 publications

(14 citation statements)

References 46 publications

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“…We previously reported that BMP signaling induces p53‐mediated apoptosis by preventing p53 degradation in the developing nasal cartilage in the caA3 mutant mice (Hayano et al, ). It is reported that rapamycin treatment can suppress p53 function to prevent apoptosis (Ding et al, ; Krzesniak, Zajkowicz, Matuszczyk, & Rusin, ), thus one potential explanation is that rapamycin treatment partially prevents cell death of Gli1 ‐expressing cells. As shown in Figure , massive cell death signals were found in vehicle treated caA3 mutant mice or rapamycin treated caA3 mutant mice from E14.5 (Tx 1) while minimal cell death was observed in the mutant mice treated by rapamycin at or from E8.5 (Tx 2 and Tx 3).…”

Section: Discussionmentioning

confidence: 99%

Rapamycin rescues BMP mediated midline craniosynostosis phenotype through reduction of mTOR signaling in a mouse model

Kramer

Yang

Swanson³

et al. 2018

Genesis

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Craniosynostosis is defined as congenital premature fusion of one or more cranial sutures. While the genetic basis for about 30% of cases is known, the causative genes for the diverse presentations of the remainder of cases are unknown. The recently discovered cranial suture stem cell population affords an opportunity to identify early signaling pathways that contribute to craniosynostosis. We previously demonstrated that enhanced BMP signaling in neural crest cells (caA3 mutants) leads to premature cranial suture fusion resulting in midline craniosynostosis. Since enhanced mTOR signaling in neural crest cells leads to craniofacial bone lesions, we investigated the extent to which mTOR signaling is involved in the pathogenesis of BMP-mediated craniosynostosis by affecting the suture stem cell population. Our results demonstrate a loss of suture stem cells in the caA3 mutant mice by the newborn stage. We have found increased activation of mTOR signaling in caA3 mutant mice during embryonic stages, but not at the newborn stage. Our study demonstrated that inhibition of mTOR signaling via rapamycin in a time specific manner partially rescued the loss of the suture stem cell population. This study provides insight into how enhanced BMP signaling regulates suture stem cells via mTOR activation.

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Section: Discussionmentioning

confidence: 99%

Rapamycin rescues BMP mediated midline craniosynostosis phenotype through reduction of mTOR signaling in a mouse model

Kramer

Yang

Swanson³

et al. 2018

Genesis

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“…A549 cells were treated overnight with two different batches of Rapamycin at equivalent dose per volume used within mice weighing 20 g. P70 S6 Kinase phosphorylation (Thr389) was induced using Actinomycin D (Sigma-Aldrich), and anti-p70 S6 phosphorylation-specific 108D2 antibody (108D2; Cell Signaling) was used for detection, as described previously (19). …”

Section: Methodsmentioning

confidence: 99%

Rapamycin Does Not Impede Survival or Induction of Antibody Responses to Primary and Heterosubtypic Influenza Infections in Mice

et al. 2016

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Impairment of immune defenses can contribute to severe influenza infections. Rapamycin is an immunosuppressive drug often used to prevent transplant rejection and is currently undergoing clinical trials for treating cancers and autoimmune diseases. We investigated whether rapamycin has deleterious effects during lethal influenza viral infections. We treated mice with two concentrations of rapamycin and infected them with A/Puerto Rico/8/1934 (A/PR8), followed by a heterosubtypic A/Hong Kong/1/68 (A/HK68) challenge. Our data show similar morbidity, mortality, and lung viral titer with both rapamycin treatment doses compared to untreated controls, with a delay in morbidity onset in rapamycin high dose recipients during primary infection. Rapamycin treatment at high dose also led to increase in percent cytokine producing T cells in the spleen. However, all infected animals had similar serum antibody responses against A/PR8. Post-A/HK68 challenge, rapamycin had no impeding effect on morbidity or mortality and had similar serum antibody levels against A/PR8 and A/HK68. We conclude that rapamycin treatment does not adversely affect morbidity, mortality, or antibody production during lethal influenza infections.

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“…52 This apoptosis may however also involve a p53-independent component, as rapamycin reportedly has a negative effect on p53 induced pro-apoptotic proteins. 25,56 Inhibition of the p53 response by mTOR inhibitors is presumably a general phenomenon and occurs in response to DNA damage, oncogenic stress and nucleolar stress as supported by previous literature. It is known that inhibition of mTOR pathway blunts the p53 transcriptional response to genotoxic stress (DNA damage).…”

Section: Discussionmentioning

confidence: 52%

“…58 Several years ago we found that caffeine and wortmannin prevented p53 stabilization by oncogenic c-Myc in normal human diploid fibroblasts. 59 It was recently shown that the AKT kinase is phosphorylated and activated by Act D. 56,60 Indeed, the AKT inhibitor MK-2206 and similar compounds attenuated activation of the p53 pathway by Act D. 56,60 Inhibitors of AKT also reduce mTOR activity since AKT functions upstream of mTOR. An important event in the activation of the p53 response to nucleolar stress may then rely on increased AKT signaling that feeds onto mTOR.…”

Section: Discussionmentioning

confidence: 99%

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mTOR inhibitors blunt the p53 response to nucleolar stress by regulating RPL11 and MDM2 levels

Goudarzi¹,

Nistér

Lindström³

2014

Cancer Biology & Therapy

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target of rapamycin; MTT, (3-[4, 5-dimethylthiazol-2-yl]-2, 5 diphenyl tetrazolium bromide); PI, propidium iodide Mechanistic target of rapamycin (mTOR) is a master regulator of cell growth through its ability to stimulate ribosome biogenesis and mRNA translation. In contrast, the p53 tumor suppressor negatively controls cell growth and is activated by a wide range of insults to the cell. The mTOR and p53 signaling pathways are connected by a number of different mechanisms. Chemotherapeutics that inhibit ribosome biogenesis often induce nucleolar stress and activation of p53. Here we have investigated how the p53 response to nucleolar stress is affected by simultaneous mTOR inhibition in osteosarcoma and glioma cell lines. We found that inhibitors of the mTOR pathway including rapamycin, wortmannin, and caffeine blunted the p53 response to nucleolar stress induced by actinomycin D. Synthetic inhibitors of mTOR (temsirolimus, LY294.002 and PP242) also impaired actinomycin D triggered p53 stabilization and induction of p21. Ribosomal protein (RPL11) is known to be required for p53 protein stabilization following nucleolar stress. Treatment of cells with mTOR inhibitors may lead to reduced synthesis of RPL11 and thereby destabilize p53. We found that rapamycin mimicked the effect of RPL11 depletion in terms of blunting the p53 response to nucleolar stress. However, the extent to which the levels of p53 and RPL11 were reduced by rapamycin varied between cell lines. Additional mechanisms whereby rapamycin blunts the p53 response to nucleolar stress are likely to be involved. Indeed, rapamycin increased the levels of endogenous MDM2 despite inhibition of its phosphorylation at Ser-166. Our findings may have implications for the design of combinatorial cancer treatments with mTOR pathway inhibitors.

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Rapamycin prevents strong phosphorylation of p53 on serine 46 and attenuates activation of the p53 pathway in A549 lung cancer cells exposed to actinomycin D

Cited by 20 publications

References 46 publications

Rapamycin rescues BMP mediated midline craniosynostosis phenotype through reduction of mTOR signaling in a mouse model

Rapamycin rescues BMP mediated midline craniosynostosis phenotype through reduction of mTOR signaling in a mouse model

Rapamycin Does Not Impede Survival or Induction of Antibody Responses to Primary and Heterosubtypic Influenza Infections in Mice

mTOR inhibitors blunt the p53 response to nucleolar stress by regulating RPL11 and MDM2 levels

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