Transcriptional Repressor Activating Transcription Factor 3 Protects Human Umbilical Vein Endothelial Cells from Tumor Necrosis Factor-α-induced Apoptosis through Down-regulation ofp53 Transcription

Kawauchi, Junya; Zhang, Chun; Nobori, Kiyoshi; Hashimoto, Yoshinori; Adachi, Mio; Noda, Asao; Sunamori, Makoto; Kitajima, Shigetaka

doi:10.1074/jbc.m202974200

Cited by 125 publications

(92 citation statements)

References 46 publications

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“…It is interesting to note that ATF3 directly binds p53 and represses the p53-dependent trans-activation of the collagenase gene promoter 29) . Kawauchi et al 30) also demonstrated that ATF3 protected endothelial cells from TNF-α-induced apoptosis by downregulating p53. Based on our TUNEL, RT-PCR and western blot findings, we propose that it is possible that since P53 expression was not significantly different from the control in the DEHP 100 mg/kg/day group (Figs.…”

Section: Discussionmentioning

confidence: 97%

Di‐(2‐ethylhexyl) Phthalate Upregulates ATF3 Expression and Suppresses Apoptosis in Mouse Genital Tubercle

Liu

Zhang

et al. 2009

Journal of Occupational Health

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Di-(2-ethylhexyl) Phthalate Upregulates ATF3 Expression and Suppresses Apoptosis in Mouse Genital Tubercle: Xing LIU, et al. Department of Pediatric Urology, Chongqing Children's Hospital, Chongqing Medical University, ChinaObjectives: To investigate the effect of di-(2-ethylhexyl) phthalate (DEHP) on the expression of activating transcription factor 3 (ATF3) and apoptosis of fetal mouse genital tubercle (GT). Methods: In this developmental toxicity study, pregnant C57BL/6 mice were exposed to corn oil or DEHP (100 or 500 mg/kg/ day) from embryonic day 12 (ED12) to ED16. Apoptosis was characterized by Terminal transferase dUTP nick end labeling (TUNEL) assay. Using RT-PCR and western blot, the expressions of ATF3 and apoptosisrelated genes (P53, Bcl-2 and Bax) were investigated. Results: Apoptosis of fetal mouse GT cells notably decreased after DEHP treatment. DEHP activated ATF3 both at the mRNA and protein levels in GT. Furthermore, pro-apoptotic P53 was downregulated and the ratio of anti-apoptotic (Bcl-2)/pro-apoptotic (Bax) was not significantly changed. Conclusions: These results suggest that DEHP may induce external genital defects via a mechanism involving apoptosis, which might correlate with the regulation of ATF3 and P53 expressions. (J Occup Health 2009; 51: 57-63)

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Section: Discussionmentioning

confidence: 97%

Di‐(2‐ethylhexyl) Phthalate Upregulates ATF3 Expression and Suppresses Apoptosis in Mouse Genital Tubercle

Liu

Zhang

et al. 2009

Journal of Occupational Health

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“…Indeed, ATF3 is normally expressed at a steady state in quiescent cells. It has traditionally been related to cell survival and/or apoptosis, stress, DNA damage, homeostasis, wound healing, cell adhesion, inflammation, nutrient limitation, and chemical exposure (32)(33)(34)(35)(36). Moreover, overexpression of ATF3 suppresses cell growth, by slowing the progression of cells from G1 to S phase, and it has been related to pro-apoptotic events and in the regulation of cell fate (36,37).…”

Section: Discussionmentioning

confidence: 99%

Activating transcription factor 3: a hormone responsive gene in the etiology of hypospadias

Beleza-Meireles

Töhönen

Söderhäll

et al. 2008

European Journal of Endocrinology

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Introduction: Hypospadias is a common inborn error of the genital development, whose complex etiology remains elusive. Defects of the androgen metabolism and activity have been found in a subset of boys with hypospadias. Moreover, the balance between androgens and estrogens seems to be important to the proper male genital development. Activating transcription factor 3 (ATF3), an estrogen responsive gene, has been reported to be expressed during sexual development and up-regulated in hypospadic genital skin. We investigated ATF3 as a candidate gene for hypospadias. Material and methods: Genotyping of eight-tagged single nucleotide polymorphisms (SNP)s was performed in 330 boys with hypospadias and in 380 healthy controls. Screening for mutations in ATF3 was conducted in a subset of boys with hypospadias. ATF3 expression was evaluated in the foreskin of boys with hypospadias and in healthy controls and in the human fetal genitalia by immunohistochemistry. Results: Three common SNPs, spanning a region of about 16 kb in intron 1 of ATF3, are associated with hypospadias. These SNPs are not linked and their effects are independent. The combination of the three risk SNPs yields the highest significance. Mutation screening identified the gene variant c536AOG in one patient and c817COT in the 3 0 -UTR in two other patients. ATF3 expression was evidenced in the developing male urethra. Conclusions: ATF3 gene variants influence the risk of hypospadias. Its hormonal responsiveness may underlie this risk effect. But also other ATF3-dependent biological aspects, such as cell survival and death, response to stress stimuli, or the control of epithelial-mesenchymal interactions, may be of importance.

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“…ATF3-and p15 PAF -expressing constructs have been described earlier. 16,28 Transfection experiments were carried out in 24-well plate (60 000) cells, using the Lipofectamine 2000 reagent (Invitrogen). When indicated, cells were UVC-irradiated (5 J/m 2 , Vilber Lourmat) the day after transfection.…”

Section: Methodsmentioning

confidence: 99%

ATF3 and p15PAF are novel gatekeepers of genomic integrity upon UV stress

et al. 2009

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After genotoxic stress, normal cells trigger DNA repair or, if unable to repair, undergo apoptosis to eradicate the cells that bear the risk of becoming tumorigenic. Here we show that repression of the transcription factor, activating transcription factor 3 (ATF3), after ultraviolet (UV)-mediated genotoxic stress impairs the DNA repair process. We provide evidence that ATF3 directly regulates the proliferating cell nuclear antigen (PCNA)-associated factor KIAA0101/p15 PAF . We further show that the expressions of ATF3 and p15 PAF is sufficient to trigger the DNA repair machinery, and that attenuation of their expression alters DNA repair mechanisms. We show that the expression of p15 PAF compensates for a lack of ATF3 expression, thereby constituting a major effector of ATF3 in the DNA repair process. In addition, we provide evidence that p15 PAF expression is required for the correct function of PCNA during DNA repair, as prevention of their interaction significantly alters DNA repair mechanisms. Finally, defective DNA repair, because of the downregulation of p15 PAF expression, rendered the cells more sensitive to UV-induced cell death. Therefore, our results suggest ATF3 and p15 PAF as novel gatekeepers of genomic integrity after UV exposure. Environmental genotoxic stress is one of the major causes of genomic instability. During such a stress, the maintenance of genomic integrity is of crucial importance to allow correct cellular function. The nucleotide excision repair (NER) machinery is responsible for recognition and incision of DNA lesions caused by ultraviolet (UV) irradiation and chemical agents. 1 Proliferating cell nuclear antigen (PCNA) is responsible for recruitment of Pold and, therefore, mediates DNA resynthesis within the site of the lesion. 1 The importance of such machinery is underscored by the numerous human syndromes, such as xeroderma pigmentosum (XP) and trichothiodystrophy (TTD), caused by the mutation of genes involved in DNA repair. Such mutations compromise genomic integrity, and XP and TTD patients are highly photosensitive and prone to develop skin tumors of keratinocyte origin, such as basal and squamous cell carcinoma. Severe defects in the DNA repair mechanism thus impair the apoptotic pathway responsible for destruction of cells that bear the risk of becoming tumorigenic. The correct DNA damage response is therefore of great importance in the maintenance of a UV-inducible anticancer barrier that elicits growth arrest, repair or cell death.Activating transcription factor 3 (ATF3) is a member of the ATF/CREB subfamily of the basic region leucine zipper (bZIP) family and may be strongly induced in a variety of tissues by different stress signals. 2 Several pathways are responsible for ATF3 induction, such as ATM and Nibrin 1, JNK and NF-kB, in a p53-dependent or -independent manner. 3-5 Induction of ATF3 often correlates with cellular damage, suggesting an important role during the cellular stress response. 6 We have recently reported that the alteration of Egr-1 expression during ...

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Transcriptional Repressor Activating Transcription Factor 3 Protects Human Umbilical Vein Endothelial Cells from Tumor Necrosis Factor-α-induced Apoptosis through Down-regulation ofp53 Transcription

Abstract: Activating transcription factor 3 (ATF3) is a transcriptional repressor that is rapidly induced in cells exposed

Cited by 125 publications

References 46 publications

Di‐(2‐ethylhexyl) Phthalate Upregulates ATF3 Expression and Suppresses Apoptosis in Mouse Genital Tubercle

Di‐(2‐ethylhexyl) Phthalate Upregulates ATF3 Expression and Suppresses Apoptosis in Mouse Genital Tubercle

Activating transcription factor 3: a hormone responsive gene in the etiology of hypospadias

ATF3 and p15PAF are novel gatekeepers of genomic integrity upon UV stress

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