Desferrioxamine (DFX) has genotoxic effects on cultured human lymphocytes and induces the p53-mediated damage response

Kim, Byeong Mo; Choi, Jun Yeol; Kim, Yang Jee; Woo, Hae Dong; Chung, Hai Won

doi:10.1016/j.tox.2006.10.022

Cited by 25 publications

(17 citation statements)

References 53 publications

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“…17 We started to detail how DFO activates DNA damage pathway. Human colorectal carcinoma HCT116 cells were treated with DFO at different concentrations for 24 h, followed by treatment with either IR-mimetic agent NCS that can produce double-stranded breaks, 4 or DNA replication inhibitor HU for 30 min or 1 h (Figures 1a and b).…”

Section: Resultsmentioning

confidence: 99%

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Phosphorylation of SMC1 by ATR is required for desferrioxamine (DFO)-induced apoptosis

Ausman

Sendo

et al. 2011

Cell Death Dis

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DNA damage signaling pathways are initiated in response to chemical reagents and radiation damage, as well as in response to hypoxia. It is implicated that structural maintenance of chromosomes 1 (SMC1) is not only a component of the cohesion complex but also facilitates the activation of DNA damage checkpoint proteins. Here, we studied the mechanism of DNA damage checkpoint activated by ATR–SMC1 pathway when cells are treated with desferrioxamine (DFO), a hypoxia-mimetic reagent. We show that DFO treatment induces phosphorylation of SMC1 at Ser966, NBS1 at Ser343, Chk1 at Ser317, Chk2 at Thr68, and p53 at Ser15. Among these sites, phosphorylation of SMC1, NBS1, and Chk1 by DFO are mediated by ATR as it is greatly reduced in both ATR-deficient human fibroblasts and HCT116 human colon cancer cells in which ATR is heterozygously mutated, whereas these proteins are phosphorylated in cells deficient for ATM and DNA-PKcs. DFO-induced apoptosis is decreased in ATR-mutant HCT116 cells, although p53 is normally activated in those cells. Expression of SMC1 S966A in which Ser966 is substituted to Ala attenuates apoptosis and phosphorylation of Chk1 at Ser317 after DFO treatment, although levels of HIF1α are not significantly changed. These results suggest that DFO induces apoptosis through the ATR–SMC1 arm of the pathway.

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Section: Resultsmentioning

confidence: 99%

“…DFO, which is used to induce hypoxia conditions, has genotoxic effects on human lymphocytes cell culture, 17 and induces apoptosis through the p38/caspase 8/Bid/Bax pathway, 24 whereas anti-apoptotic functions of DFO has also been observed in erythrocytes. 26 Thus, regulation of apoptosis by DFO is cell context-dependent.…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation of SMC1 by ATR is required for desferrioxamine (DFO)-induced apoptosis

Ausman

Sendo

et al. 2011

Cell Death Dis

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“…Recently, we reported that desferrioxamine is able to mimic hypoxia and trigger p53-dependent DNA-damage checkpoints in human lymphocytes [10]. These results prompted us to examine the mechanism by which hypoxia and reoxygenation cause cytotoxicity in human lymphocytes.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, Yazdi et al [9] reported that the ATM/NBS1/SMC1 pathway is a separate branch of the S‐phase checkpoint pathway, distinct from the ATM/CHK2/CDC25A branch. It was previously demonstrated that the hypoxia‐mimic desferrioxamine (DFX) could induce p53‐dependent checkpoint signals in cultured lymphocytes [10]. Our objective was to examine the role of DNA damage‐responsive proteins in the induction of checkpoint pathways that might be involved in cell cycle arrest during H/R.…”

Section: Introductionmentioning

confidence: 99%

Reoxygenation following hypoxia activates DNA‐damage checkpoint signaling pathways that suppress cell‐cycle progression in cultured human lymphocytes

et al. 2007

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Cellular responses to DNA damage after hypoxia and reoxygenation (H/R) were examined in human lymphocytes. Cultured lymphocytes exposed to H/R showed a lower cytokinesis block proliferation index and a higher frequency of micronuclei in comparison to control cells. Western blots showed that H/ R exposure induced p53 expression; however, p21 and Bax expression did not increase, indicating that H/R did not affect p53 transactivational activity. Phosphorylation of p53 (Ser15), Chk1 (Ser345), and Chk2 (Thr68) was also observed, suggesting that H/R activates p53 through checkpoint signals. In addition, H/R exposure caused the phosphorylation and negative regulation of Cdc2 and Cdc25C, proteins that are involved in cell-cycle arrest at the G2/M checkpoint. The S-phase checkpoint, regulated by the ATM-p95/NBS1-SMC1 pathway, was also triggered in H/R-exposed lymphocytes. These results demonstrate that H/R exposure triggers checkpoint signaling and induces cell-cycle arrest in cultured human lymphocytes.

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“…Iron is thought to interact to LYR motifs 84 and not to CXXC motifs like copper and zinc and is therefore not expected to directly interfere in zinc binding to p53. However, many groups have shown that iron chelation can stabilize p53 and promote p53 dependent transcription, whereas iron overload actively facilitates p53 degradation [85][86][87][88][89][90] . However, many groups have shown that iron chelation can stabilize p53 and promote p53 dependent transcription, whereas iron overload actively facilitates p53 degradation [85][86][87][88][89][90] .…”

Section: Ironmentioning

confidence: 99%

Metal toxicity and the p53 protein: an intimate relationship

Phatak

Müller

2015

Toxicol. Res.

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Many metals are pivotal for the function of enzymes and proteins, but in excess can result in the formation of free radicals (ROS) that can cause damage to DNA. p53 is a tumour suppressor protein and transcription factor that can react to DNA damage to either facilitate a repair response or when the damage is too severe to initiate apoptosis and cell death.ROS can therefore activate p53, but the p53 protein itself is susceptible to oxidative changes, resulting in unfolding of the p53 protein and therefore loss of activity. In order to be active, p53 needs to bind zinc while other metals such as copper can displace zinc leading to p53 unfolding. Metal exposure can therefore result in the activation or inactivation of p53 directly and indirectly through ROS, all dependent on the type of metal and the severity of the exposure. Conversely, p53 itself can impact on ROS and affect the expression of important proteins in metal cell biology. In the current review, we have summarized the relationship between p53, ROS and metal toxicity.

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Desferrioxamine (DFX) has genotoxic effects on cultured human lymphocytes and induces the p53-mediated damage response

Cited by 25 publications

References 53 publications

Phosphorylation of SMC1 by ATR is required for desferrioxamine (DFO)-induced apoptosis

Phosphorylation of SMC1 by ATR is required for desferrioxamine (DFO)-induced apoptosis

Reoxygenation following hypoxia activates DNA‐damage checkpoint signaling pathways that suppress cell‐cycle progression in cultured human lymphocytes

Metal toxicity and the p53 protein: an intimate relationship

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