AKT mediates actinomycin D-induced p53 expression

Cheng, Chen-Li; Ho, Dong-Ru; Chen, Fei-Yun; Chen, Changrong; Ke, Yu-De; Su, Jyan-Gwo J.

doi:10.18632/oncotarget.1328

Cited by 31 publications

(25 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The cells were treated with 2 % isoflurane, plus 21 % O 2 and 5 % CO 2 , for a duration of 6 h as described by Xie et al [4] and Zhang et al [39] in the studies. Fifty μM Z-VAD-FMK (Z-VAD, Abcam Plc, Cambridge, UK), 1 mM N-acetyl-L-cysteine (NAC, Sigma-Aldrich Corporation, St. Louis, MO), 100 ng/ml actinomycin D [p53 activator [40], Santa Cruz Biotechnology, Santa Cruz, CA], or 10 ng/ml pifithrin-α [p53 inhibitor [41], Sigma-Aldrich Corporation, St. Louis, MO] was given to the cells 60 min before the isoflurane treatment.…”

Section: Methodsmentioning

confidence: 99%

Anesthetic Isoflurane Induces DNA Damage Through Oxidative Stress and p53 Pathway

Dong

et al. 2016

Mol Neurobiol

View full text Add to dashboard Cite

DNA damage is associated with aging and neurological disorders, including Alzheimer’s disease. Isoflurane is a commonly used anesthetic. It remains largely unknown whether isoflurane induces DNA damage. Phosphorylation of the histone protein H2A variant X at Ser139 (γH2A.X) is a marker of DNA damage. We therefore set out to assess the effects of isoflurane on γH2A.X level in H4 human neuroglioma cells and in brain tissues of mice. Oxidative stress, caspase-activated DNase (CAD), and the p53 signaling pathway are involved in DNA damage. Thus, we determined the interaction of isoflurane with reactive oxygen species (ROS), CAD, and p53 to illustrate the underlying mechanisms. The cells were treated with 2 % isoflurane for 3 or 6 h. The mice were anesthetized with 1.4 % isoflurane for 2 h. Western blot, immunostaining and live cell fluorescence staining were used in the experiments. We showed that isoflurane increased levels of γH2A.X, cleaved caspase-3, and nucleus translocation of CAD and decreased levels of inhibitor of CAD (ICAD) and p53. Isoflurane enhanced the nucleus level of γH2A.X. Moreover, caspase inhibitor Z-VAD and ROS generation inhibitor N-acetyl-L-cysteine (NAC) attenuated the isoflurane-induced increase in γH2A.X level. However, NAC did not significantly alter the isoflurane-induced reduction in p53 level. Finally, p53 activator (actinomycin D) and inhibitor (pifithrin-α) attenuated and potentiated the isoflurane-induced increase in γH2A.X level, respectively. These findings suggest that isoflurane might induce DNA damage, as represented by increased γH2A.X level, via induction of oxidative stress and inhibition of the repair of DNA damage through the p53 signaling pathway.

show abstract

Section: Methodsmentioning

confidence: 99%

Anesthetic Isoflurane Induces DNA Damage Through Oxidative Stress and p53 Pathway

Dong

et al. 2016

Mol Neurobiol

View full text Add to dashboard Cite

show abstract

“…Low doses of Act D (<10 nM) have been shown to exclusively inhibit RNA Polimerase I activity, leading to impaired ribosomal RNA (rRNA) transcription. 8 The mode of action and specific targets involved in the molecular pathways activated by Act D are less defined. The identification of the cellular targets of a chemotherapeutic drug is an important challenge for the improvement of therapy regimens for cancer treatment.…”

Section: Introductionmentioning

confidence: 99%

Regulatory role of rpL3 in cell response to nucleolar stress induced by Act D in tumor cells lacking functional p53

et al. 2016

View full text Add to dashboard Cite

Many chemotherapeutic drugs cause nucleolar stress and p53-independent pathways mediating the nucleolar stress response are emerging. Here, we demonstrate that ribosomal stress induced by Actinomycin D (Act D) is associated to the up-regulation of ribosomal protein L3 (rpL3) and its accumulation as ribosome-free form in lung and colon cancer cell lines devoid of p53. Free rpL3 regulates p21 expression at transcriptional and post-translational levels through a molecular mechanism involving extracellular-signal-regulated kinases1/2 (ERK1/2) and mouse double minute-2 homolog (MDM2). Our data reveal that rpL3 participates to cell response acting as a critical regulator of apoptosis and cell migration. It is noteworthy that silencing of rpL3 abolishes the cytotoxic effects of Act D suggesting that the loss of rpL3 makes chemotherapy drugs ineffective while rpL3 overexpression associates to a strong increase of Act D-mediated inhibition of cell migration. Taking together our results show that the efficacy of Act D chemotherapy depends on rpL3 status revealing new specific targets involved in the molecular pathways activated by Act D in cancers lacking of p53. Hence, the development of treatments aimed at upregulating rpL3 may be beneficial for the treatment of these cancers.

show abstract

“…Los M et al 27 also reported that Akt activation can increase intracellular oxygen consumption and ROS production, resulting in ROS sensitive cells apoptosis. In addition, some finding revealed a function of Akt in the upregulation of actinomycin D-induced p53 expression 28 and p53 participates in the induction of apoptosis by promoting ROS production 29 . Our previous study also demonstrated that p53 levels are higher in whole blood samples of KBD patients 8 .…”

Section: Discussionmentioning

confidence: 99%

Role of selenoprotein S (SEPS1) -105G>A polymorphisms and PI3K/Akt signaling pathway in Kashin-Beck disease

Wang

Dai

et al. 2015

Osteoarthritis and Cartilage

View full text Add to dashboard Cite

show abstract

AKT mediates actinomycin D-induced p53 expression

Cited by 31 publications

References 45 publications

Anesthetic Isoflurane Induces DNA Damage Through Oxidative Stress and p53 Pathway

Anesthetic Isoflurane Induces DNA Damage Through Oxidative Stress and p53 Pathway

Regulatory role of rpL3 in cell response to nucleolar stress induced by Act D in tumor cells lacking functional p53

Role of selenoprotein S (SEPS1) -105G>A polymorphisms and PI3K/Akt signaling pathway in Kashin-Beck disease

Contact Info

Product

Resources

About