The role of ATF‐2 in oncogenesis

Vlahopoulos, Spiros; Logotheti, Stella; Mikas, Dimitris; Giarika, Athina; Gorgoulis, Vassilis G.; Zoumpourlis, Vassilis

doi:10.1002/bies.20734

Cited by 112 publications

(92 citation statements)

References 100 publications

(84 reference statements)

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“…We also showed that NFATc, ATF2, and c-Jun induce Angptl2 expression, providing a mechanism for tumor cell ANGPTL2 induction. These findings are consistent with previous reports showing that activation of ATF/CREB family proteins and/or the calcineurin/NFATc pathway occurs in aggressively advanced tumors (6,19,28,29). We have reported that obese adipose tissue-related endoplasmic reticulum (ER) stress increases ANGPTL2 secretion or expression in adipocytes (13).…”

Section: Discussionsupporting

confidence: 93%

Tumor Cell–Derived Angiopoietin-like Protein ANGPTL2 Is a Critical Driver of Metastasis

et al. 2012

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Strategies to inhibit metastasis have been mainly unsuccessful in part due to insufficient mechanistic understanding. Here, we report evidence of critical role for the angiopoietin-like protein 2 (ANGPTL2) in metastatic progression. In mice, Angptl2 has been implicated in inflammatory carcinogenesis but it has not been studied in human tumors. In patients with lung cancer, elevated levels of ANGPTL2 expression in tumor cells within the primary tumor were associated with a reduction in the period of disease-free survival after surgical resection. Transcription factors NFATc, ATF2, and c-Jun upregulated in aggressive tumor cells promoted increased Angptl2 expression. Most notably, tumor cell-derived ANGPTL2 increased in vitro motility and invasion in an autocrine/paracrine manner, conferring an aggressive metastatic tumor phenotype. In xenograft mouse models, tumor cell-derived ANGPTL2 accelerated metastasis and shortened survival whereas attenuating ANGPTL2 expression in tumor cells-blunted metastasis and extended survival. Overall, our findings showed that tumor cell-derived ANGPTL2 drives metastasis and provided an initial proof of concept for blockade of its action as a strategy to antagonize the metastatic process. Cancer Res; 72(7); 1784-94. Ó2012 AACR.

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Section: Discussionsupporting

confidence: 93%

Tumor Cell–Derived Angiopoietin-like Protein ANGPTL2 Is a Critical Driver of Metastasis

et al. 2012

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“…This interaction is finely tuned by several stimuli and it is responsible for different cellular response ranging from apoptosis to proliferation. 7,9,36 One of the crucial partners of this dimeric complex is the proto-oncogene cJUN. The JNK/c-Jun/ ATF2 pathway regulates a plethora of target genes containing AP1-binding sites, including those that controlling survival and apoptosis, metalloproteinases and nuclear hormone receptors.…”

Section: Discussionmentioning

confidence: 99%

“…5,6 Independent of its transcriptional activity, ATF2 also plays an important role in the DNA damage response and in the regulation of intra-S-phase checkpoint (reviewed in Ref. 7). Several studies reported a correlation between ATF2/JNK-mediated activation and resistance to DNA damaging agents.…”

mentioning

confidence: 99%

ATF2 contributes to cisplatin resistance in non‐small cell lung cancer and celastrol induces cisplatin resensitization through inhibition of JNK/ATF2 pathway

Iacono

Monica

Vavalà

et al. 2014

Intl Journal of Cancer

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ATF2 is a transcription factor involved in stress and DNA damage. A correlation between ATF2 JNK-mediated activation and resistance to damaging agents has already been reported. The purpose of the present study was to investigate whether ATF2 may have a role in acquired resistance to cisplatin in non-small cell lung cancer (NSCLC). mRNA and protein analysis on matched cancer and corresponding normal tissues from surgically resected NSCLC have been performed. Furthermore, in NSCLC cell lines, ATF2 expression levels were evaluated and correlated to platinum (CDDP) resistance. Celastrol-mediated ATF2/cJUN activity was measured. High expression levels of both ATF2 transcript and proteins were observed in lung cancer specimens (p << 0.01, Log 2 (FC) 5 14.7). CDDP-resistant NSCLC cell lines expressed high levels of ATF2 protein. By contrast, Celastrol-mediated ATF2/cJUN functional inhibition restored the response to CDDP. Moreover, ATF2 protein activation correlates with worse outcome in advanced CDDP-treated patients. For the first time, it has been shown NSCLC ATF2 upregulation at both mRNA/protein levels in NSCLC. In addition, we reported that in NSCLC cell lines a correlation between ATF2 protein expression and CDDP resistance occurs. Altogether, our results indicate a potential increase in CDDP sensitivity, on Celastrolmediated ATF2/cJUN inhibition. These data suggest a possible involvement of ATF2 in NSCLC CDDP-resistance.Non-small cell lung cancer (NSCLC) is characterized by high incidence and mortality rate worldwide, being the most common subtypes represented by adenocarcinoma and squamous cell carcinoma. 1 Platinum-based chemotherapy in combination with other cytotoxic agents such as Gemcitabine, taxanes and vinorelbine represented the standard of care for unselected patients with advanced NSCLC. Recently, in nonsquamous histology, the combination of cisplatin (CDDP) and pemetrexed showed superior activity. 2,3 However, in chemotherapy-treated NSCLC, the duration of response is relatively short due to primary or acquired resistance to chemotherapy. 4 Patients with advanced disease may not derive any benefit from first-line chemotherapy, while they face significant treatment-related side effects. Consequently, it appears a logical approach to investigate alternative ways to increase the effectiveness outcomes of chemotherapy, through the identification of molecular features suggestive of a better therapeutic ratio.Activating transcription factor 2 (ATF2) is a member of the basic helix-loop-helix (b-ZIP) transcription factor family, whose transcriptional activities are mediated by stressactivated kinases JNK/p38 and activated by phosphorylation on threonine residues. 5,6 Independent of its transcriptional activity, ATF2 also plays an important role in the DNA damage response and in the regulation of intra-S-phase checkpoint (reviewed in Ref. 7). Several studies reported a correlation between ATF2/JNK-mediated activation and resistance to DNA damaging agents. Hayakawa et al. showed that stable expression of ATF...

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“…In addition, mitogen-activated protein kinase 14 (p38) mitogen-activated protein kinase (MAPK) was activated by AOH in NIH3T3 cells (12). Activating transcription factor 2 (ATF2) is one of the downstream molecules of the MAPK signal pathway and can be activated by p38MAPK and mitogen-activated protein kinase 8 (JNK) (13,14). ATF2 is a member of ATF or cAMP-responsive element binding protein (CREB) family, which contains the basic/leucine zipper motifs (bZIP) and can bind to cAMP-responsive elements (CREs) (15,16).…”

Section: Introductionmentioning

confidence: 99%

Involvement of p38MAPK-ATF2 signaling pathway in alternariol induced DNA polymerase β expression

Zhao

Lü

et al. 2016

Oncology Letters

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Abstract. Base excision repair (BER) systems are important for maintaining the integrity of genomes in mammalian cells. Aberrant DNA bases or broken single strands can be repaired by BER. Consequently, DNA lesions, which may be caused by cancer and aging, have a close association with BER procedure. DNA polymerase β (polβ) is a critical BER enzyme that can excise 5'-sugar phosphate prior to adding a nucleotide in the gap by its function as a DNA polymerase in the BER process. However, DNA polβ is an error-prone DNA polymerase, and overexpressing polβ increases the cellular spontaneous mutation rate. DNA polβ overexpression has been identified in various human tumors, which implies that DNA polβ overexpression has a close association with tumorigenesis. The present study showed that alternariol (AOH), a secondary product of a fungus that is found in grains and fruits, could cause DNA damage to NIH3T3 cells in a single cell gel electrophoresis, and that 2, 10 and 20 µM AOH induced DNA polβ overexpression in a dose-dependent manner. In the process, the level of phosphorylation of mitogen-activated protein kinase 14 (p38) mitogen-activated protein kinase (MAPK) and activating transcription factor 2 (ATF2) was increased. In addition, SB203580, a p38MAPK inhibitor, resulted in decreased DNA polβ expression. Small hairpin RNA-p38MAPK had the same effect; notably, DNA polβ expression was downregulated in p38MAPK knockdown cells. These data suggest that the p38MAPK-ATF2 signaling pathway may be involved in DNA polβ expression induced by AOH.

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The role of ATF‐2 in oncogenesis

Cited by 112 publications

References 100 publications

Tumor Cell–Derived Angiopoietin-like Protein ANGPTL2 Is a Critical Driver of Metastasis

Tumor Cell–Derived Angiopoietin-like Protein ANGPTL2 Is a Critical Driver of Metastasis

ATF2 contributes to cisplatin resistance in non‐small cell lung cancer and celastrol induces cisplatin resensitization through inhibition of JNK/ATF2 pathway

Involvement of p38MAPK-ATF2 signaling pathway in alternariol induced DNA polymerase β expression

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