Influence of ionizing radiation on proliferation, c-myc expression and the induction of apoptotic cell death in two breast tumour cell lines differing in p53 status

Watson, N. C.; Di, Yongmei; Orr, Michael S.; Fornari, Frank A.; Randolph, Joyce K.; Magnet, K. J.; Jain, Pramod T.; Gewirtz, David A.

doi:10.1080/095530097143059

Cited by 34 publications

(5 citation statements)

References 34 publications

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“…However, the results of this report suggest that IR-induced G 2 /M cell-cycle arrest as well as the regulation of Rac1 on the IR-induced G 2 /M checkpoint response is apparently independent of p53, as among the four breast cancer cell lines used for the studies, MDA-MB-231 and T47D cells express mutant p53 [56], whereas MCF-7 and ZR75-1 express wild-type p53. Consistent with our observation, results from other studies also show that p53 status has no influence on IR-induced G 2 /M cycle arrest [57]. …”

Section: Discussionsupporting

confidence: 93%

RAC1 GTPase plays an important role in γ-irradiation induced G2/M checkpoint activation

et al. 2012

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IntroductionIn response to gamma-irradiation (IR)-induced double-strand DNA breaks, cells undergo cell-cycle arrest, allowing time for DNA repair before reentering the cell cycle. G2/M checkpoint activation involves activation of ataxia telangiectasia mutated (ATM)/ATM- and rad3-related (ATR) kinases and inhibition of Cdc25 phosphatases, resulting in inhibition of Cdc2 kinase and subsequent G2/M cell-cycle arrest. Previous studies from our laboratory showed that the G2/M checkpoint activation after IR exposure of MCF-7 breast cancer cells is dependent on the activation of extracellular signal-regulated protein kinase 1 and 2 (ERK1/2) signaling. In the present studies, we investigated the role of Ras-related C3 botulinum toxin substrate 1 (Rac1) guanosine triphosphatase (GTPase) in IR-induced G2/M checkpoint response and ERK1/2 activation, as well as in cell survival after IR.MethodsWith Rac1-specific inhibitor, dominant negative mutant Rac1 (N17Rac1) and specific small interfering RNA, the effect of Rac1 on IR-induced G2/M checkpoint response and ERK1/2 activation was examined in human breast cancer cells. In addition, the effect of Rac1 on cell survival after irradiation was assessed by using Rac1-specific inhibitor.ResultsIR exposure of MCF-7 breast cancer cells was associated with a marked activation of Rac1 GTPase. Furthermore, inhibition of Rac1 by using specific inhibitor, dominant-negative Rac1 mutant, or specific siRNA resulted in attenuation of IR-induced G2/M arrest and concomitant diminution of IR-induced activation of ATM, ATR, Chk1, and Chk2 kinases, as well as phosphorylation of Cdc2-Tyr15. Moreover, Rac1 inhibition or decreased Rac1 expression also abrogated IR-induced phosphorylation of mitogen-activated protein kinase kinase 1 and 2 (MEK1/2) and ERK1/2. Ultimately, inhibition of Rac1 markedly increased cellular sensitivity to IR exposure, which involves induction of apoptosis.ConclusionStudies in this report suggest that Rac1 GTPase plays an essential role in the activation of IR-induced ERK1/2 signaling and subsequent G2/M checkpoint response. Furthermore, results also support a role for Rac1 in promoting cell survival after irradiation treatment.

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Section: Discussionsupporting

confidence: 93%

RAC1 GTPase plays an important role in γ-irradiation induced G2/M checkpoint activation

et al. 2012

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“…The 1570 upregulated genes contain 7 MYC target genes (FDR < 4.22 × 10 − 7 ), consistent with the fact that MYC is a direct regulator of ribosome biogenesis [67]. This agrees with reports of the involvement of MYC in radiation treatment [68, 69], suggesting MYC may trigger proliferation pathways upon genotoxic stress, in the absence of p53.…”

Section: Resultssupporting

confidence: 84%

iDEP: an integrated web application for differential expression and pathway analysis of RNA-Seq data

2018

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BackgroundRNA-seq is widely used for transcriptomic profiling, but the bioinformatics analysis of resultant data can be time-consuming and challenging, especially for biologists. We aim to streamline the bioinformatic analyses of gene-level data by developing a user-friendly, interactive web application for exploratory data analysis, differential expression, and pathway analysis.ResultsiDEP (integrated Differential Expression and Pathway analysis) seamlessly connects 63 R/Bioconductor packages, 2 web services, and comprehensive annotation and pathway databases for 220 plant and animal species. The workflow can be reproduced by downloading customized R code and related pathway files. As an example, we analyzed an RNA-Seq dataset of lung fibroblasts with Hoxa1 knockdown and revealed the possible roles of SP1 and E2F1 and their target genes, including microRNAs, in blocking G1/S transition. In another example, our analysis shows that in mouse B cells without functional p53, ionizing radiation activates the MYC pathway and its downstream genes involved in cell proliferation, ribosome biogenesis, and non-coding RNA metabolism. In wildtype B cells, radiation induces p53-mediated apoptosis and DNA repair while suppressing the target genes of MYC and E2F1, and leads to growth and cell cycle arrest. iDEP helps unveil the multifaceted functions of p53 and the possible involvement of several microRNAs such as miR-92a, miR-504, and miR-30a. In both examples, we validated known molecular pathways and generated novel, testable hypotheses.ConclusionsCombining comprehensive analytic functionalities with massive annotation databases, iDEP (http://ge-lab.org/idep/) enables biologists to easily translate transcriptomic and proteomic data into actionable insights.Electronic supplementary materialThe online version of this article (10.1186/s12859-018-2486-6) contains supplementary material, which is available to authorized users.

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“…Moreover, Fbw7 ubiquitin ligase mediates MYC degradation in response to DNA damage due to the USP28 disassociation from Fbw7 [ 18 ], which is required for MYC stability [ 233 ]. Exposure of MCF-7 breast tumor cell line to DNA-damaging agents such as topoisomerase II inhibitors VM-26, m-AMSA, and doxorubicin, or ionizing radiation is capable of suppressing MYC mRNA [ 234 – 237 ]. Moreover, continuous treatment of MCF-7 with VM-26 suppresses both mRNA and protein levels of MYC, and its transcriptional activity in response to sustained DNA damage [ 238 ].…”

Section: The Role Of Myc In Dna Damage Responsementioning

confidence: 99%

MYC: a multipurpose oncogene with prognostic and therapeutic implications in blood malignancies

et al. 2021

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MYC oncogene is a transcription factor with a wide array of functions affecting cellular activities such as cell cycle, apoptosis, DNA damage response, and hematopoiesis. Due to the multi-functionality of MYC, its expression is regulated at multiple levels. Deregulation of this oncogene can give rise to a variety of cancers. In this review, MYC regulation and the mechanisms by which MYC adjusts cellular functions and its implication in hematologic malignancies are summarized. Further, we also discuss potential inhibitors of MYC that could be beneficial for treating hematologic malignancies.

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Influence of ionizing radiation on proliferation, c-myc expression and the induction of apoptotic cell death in two breast tumour cell lines differing in p53 status

Cited by 34 publications

References 34 publications

RAC1 GTPase plays an important role in γ-irradiation induced G2/M checkpoint activation

RAC1 GTPase plays an important role in γ-irradiation induced G2/M checkpoint activation

iDEP: an integrated web application for differential expression and pathway analysis of RNA-Seq data

MYC: a multipurpose oncogene with prognostic and therapeutic implications in blood malignancies

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