Mechanism of diepoxybutane‐induced p53 regulation in human cells

Yadavilli, Sridevi; Chen, Zhenping; Albrecht, Thomas; Muganda, Perpetua M.

doi:10.1002/jbt.20300

Cited by 7 publications

(14 citation statements)

References 68 publications

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“…ATM is recognized as an important regulator of p53 checkpoint function, as ATM-deficient cells fail to induce or stabilize p53 protein levels in response to some types of DNA damage, such as ionizing radiation. This may be particularly relevant to environmental carcinogens, as transforming growth factor-beta ATM-deficient lymphoblasts exposed to the chemical diepoxybutane are unable to stabilize p53 protein levels to the same extent as cells with wild-type ATM (15). Thus, although many p53-independent functions exist for ATM, disruption of p53 growth-inhibitory checkpoint function is a major mechanism by which ATM-deficient cancer cells fail to respond to DNAdamaging agents, including specific environmental pollutants.…”

Section: P53mentioning

confidence: 99%

Mechanisms of environmental chemicals that enable the cancer hallmark of evasion of growth suppression

Nahta

Al-Mulla

Al-Temaimi

et al. 2015

CARCIN

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As part of the Halifax Project, this review brings attention to the potential effects of environmental chemicals on important molecular and cellular regulators of the cancer hallmark of evading growth suppression. Specifically, we review the mechanisms by which cancer cells escape the growth-inhibitory signals of p53, retinoblastoma protein, transforming growth factor-beta, gap junctions and contact inhibition. We discuss the effects of selected environmental chemicals on these mechanisms of growth inhibition and cross-reference the effects of these chemicals in other classical cancer hallmarks.

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Section: P53mentioning

confidence: 99%

Mechanisms of environmental chemicals that enable the cancer hallmark of evasion of growth suppression

Nahta

Al-Mulla

Al-Temaimi

et al. 2015

CARCIN

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“…Accordingly, Vijayakumaran et al (2015) showed that dysfunction of p53 occurs in half the cases of cancers by direct mutations in the gene, whereas in the remainder, p53 becomes dysfunctional through a variety of regulatory mechanisms. For example, p53 protein stability is regulated by specific kinase pathways, including the Ataxia-Telangiectasia-mutated (ATM)-checkpoint kinase 2 (Chk2) pathway, as ATM-deficient cells fail to induce or stabilize p53 protein levels in response to some types of DNA damage, such as ionizing radiation and some environmental carcinogens (Yadavilli et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Altered tumor suppressor genes expression in Egyptian pesticide applicators exposed to organophosphate insecticides

et al. 2020

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Occupational exposure in spraying and application of non-arsenical insecticides has been classified as a probable human carcinogen. The fundamental molecular mechanisms involved the tumor-related genes. This study aimed to investigate the carcinogenesis effects related to chronic exposure to organophosphate (OP) pesticides in pesticide applicators. This was a cross-sectional study conducted on 27 pesticide applicators and 24 matched controls through the period from June to December 2018. The level of acetylcholinesterase (AChE) was determined and the effects of OPs exposure on messenger RNA (mRNA) expression of the DNA-damage responsive genes P53, P21, GADD45a, and MDM2 were determined using real-time quantitative polymerase chain reaction. A significant reduction of serum AChE enzyme activities was observed in chronically exposed subjects in comparison with the control group ( p = 0.001). The expression of P53, P21 mRNA was significantly downregulated in the exposed group compared with the healthy nonexposed control group ( p < 0.05). Conversely, the expression of MDM2 and GADD45a did not significantly differ between the exposed subjects and the control group ( p > 0.05). No significant differences were noted between the exposed and control groups regarding the genotype or allele distributions of P53 Arg72Pro polymorphism. These results suggested that chronic exposure to OP insecticides may have mitogenic and carcinogenicity activity for the exposed cases due to downregulation of P53 and P21 but did not demonstrate any DNA damage properties for the exposed cases, and finally, a regular follow-up of the exposed cases for tumor markers is recommended.

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“…This was performed essentially as previously described. 17,40 Cells were placed in fresh media 24 h prior to each experiment. Cells were then washed and seeded in fresh media at a density of 2.0 × 10 5 cells/mL, prior to the addition of 10-µM DEB or vehicle for 24 and 48 h. All DEB dilutions were performed in RPMI.…”

Section: Methodsmentioning

confidence: 99%

“…Western blot analysis was utilized to determine the levels of activated phospho-ERK1/2(Thr202/Tyr204), activated phospho-MEK1/2(ser217/221), phospho-p53 (serine-15), total ERK1/2, p53, and GAPDH in all extracts. The procedure was performed as previously described, 17,40 and as modified for fluorescent antibody imaging on the Li-Cor Odyssey system (Li-Cor, Inc., Lincoln, NE), according to the system manufacturer’s instructions. Briefly, experimental and control cells were harvested and lysed by gentle vortexing at 4°C in TBSTDS (10-mM tris, (pH 7.5), 150-mM sodium chloride, 1-mM EDTA, 1% triton X-100, 0.5% sodium deoxycholate, 0.5% sodium-dodecyl-sulfate (SDS), 0.02% sodium azide, and 0.0004% sodium fluoride) supplemented with protease inhibitors (1-mM phenylmethylsufonyl fluoride, 2-μg/mL aprotinin, and 0.1-mM leupeptin) and a phosphatase inhibitor cocktail (2.5-mM sodium pyrophosphate, 1-mM sodium orthovanadate, 25-mM sodium fluoride, and 2-mM β-glycerol-phosphate).…”

Section: Methodsmentioning

confidence: 99%

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Diepoxybutane-induced apoptosis is mediated through the ERK1/2 pathway

et al. 2018

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Diepoxybutane (DEB) is the most potent active metabolite of butadiene, a regulated air pollutant. We previously reported the occurrence of DEB-induced, p53-dependent, mitochondrial-mediated apoptosis in human lymphoblasts. The present study investigated the role of the extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) pathway in DEB-induced apoptotic signaling in exposed human lymphoblasts. Activated ERK1/2 and mitogen-activated protein (MAP) kinase/ERK1/2 kinase (MEK) levels were significantly upregulated in DEB-exposed human lymphoblasts. The MEK inhibitor PD98059 and ERK1/2 siRNA significantly inhibited apoptosis, ERK1/2 activation, as well as p53 and phospho-p53 (serine-15) levels in human lymphoblasts undergoing DEB-induced apoptosis. Collectively, these results demonstrate that DEB induces apoptotic signaling through the MEK-ERK1/2-p53 pathway in human lymphoblasts. This is the first report implicating the activation of the ERK1/2 pathway and its subsequent role in mediating DEB-induced apoptotic signaling in human lymphoblasts. These findings contribute towards the understanding of DEB toxicity, as well as the signaling pathways mediating DEB-induced apoptosis in human lymphoblasts.

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Mechanism of diepoxybutane‐induced p53 regulation in human cells

Cited by 7 publications

References 68 publications

Mechanisms of environmental chemicals that enable the cancer hallmark of evasion of growth suppression

Mechanisms of environmental chemicals that enable the cancer hallmark of evasion of growth suppression

Altered tumor suppressor genes expression in Egyptian pesticide applicators exposed to organophosphate insecticides

Diepoxybutane-induced apoptosis is mediated through the ERK1/2 pathway

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