Distinct roles of Jun : Fos and Jun : ATF dimers in oncogenesis

Dam, Hans van; Castellazzi, Marc

doi:10.1038/sj.onc.1204239

Cited by 419 publications

(314 citation statements)

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“…8 Furthermore, cJUN/ATF2 complex play a role in cell transformation by inducing anchorage and/ or growth factor-independent proliferation. 9 Similar findings were also reported in melanoma and, in this type of tumor, ATF2 nuclear localization is associated with poor prognosis. 10 Celastrol, a triterpene known as tripterine, is an ingredient extracted from a plant and traditional Chinese medicine uses it as an anti-inflammatory agent.…”

supporting

confidence: 74%

“…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%

“…41 A relationship between cJUN/ ATF2 complex and growth factors independent cellular proliferation in chick embryo fibroblasts has been reported. 9 It has been observed that ATF2 affects the transcription of around 180 genes following treatment with CDDP and mostly the genes were activated via ATF2/cJUN complex. 36 As a follow up investigation, Celastrol was added for 15 hr to the CDDP-resistant cell line H522; it has been shown that Celastrol inhibits the expression of some genes involved in DNA repair, proliferation and platinum resistance (Supporting Information Table 3).…”

Section: Discussionmentioning

confidence: 99%

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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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supporting

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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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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“…AP-1 becomes activated upon a whole variety of extra/intracellular stimuli including growth factors, cytokines, tumor promoters and oncogenes (Karin et al 1997). The decision, however, which targeted genes finally turns out to be induced, is dependent on AP-1 composition (van Dam and Castellazzi 2001). Overexpression of the proto-oncogene c-fos has been demonstrated in different cancers and is known to correlate with the carcinogenesis, for example, the extent of c-fos expression is associated with the clinical degree and progression of pancreatic cancer (Lee and Charalambous 1994).…”

Section: Discussionmentioning

confidence: 99%

Growth Inhibitory Effect of the Ternary Complex Factor Net on Human Pancreatic Carcinoma Cell Lines

Zhu

et al. 2008

Tohoku J. Exp. Med.

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Pancreatic carcinoma is one of the most aggressive malignancies and carries the most dismal prognoses of all cancers. A better understanding of the genes involving in tumor development may allow us to tackle this rapidly progressive disease. The Net gene belongs to the ternary complex transcription factor (TCF) family and is regulated by the Ras/mitogen-activited protein kinase-signaling pathway. Under basal conditions, Net shows strong represssing function on transcription of proto-oncogene gene c-fos. Moreover, the lower expression of Net has been noted in some carcinoma cells, such as cervical cancer. To study the effect of Net on c-fos expression and its potential role in the growth of pancreatic carcinoma, we developed a recombinant plasmid, a pEGFP-N1-Net, which codes for Net-EGFP fusion proteins, and stably transfected it into BxPC-3 human pancreatic carcinoma cells. Using stable transformants, we were able to show that overexpression of Net decreased the expression of c-fos and inhibited pancreatic cancer cell proliferation. Cell cycle analysis demonstrated that Net overexpression inhibited cell cycle progression. These findings suggested that loss of Net repression could augment c-fos expression and further trigger neoplastic cell proliferation, which was involved in the pathogenesis of pancreatic cancer. Therefore, Net might be a potential target for the treatment of c-fos-positive pancreatic cancer.

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“…None of the CTF/NFIlike sites had an effect on MKP-1 regulation. However, the CRE/AP-1 box (TGACGTCT), which has been reported to be involved in the regulation of several genes [43], was critical. This box is also present in the promoter of the human gene [36].…”

Section: Mkp-1 Expression Induced By M-csf or Lps Is Regulated By A Cmentioning

confidence: 99%

CREB and AP‐1 activation regulates MKP‐1 induction by LPS or M‐CSF and their kinetics correlate with macrophage activation versus proliferation

et al. 2009

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MAPK phosphatase-1 (MKP-1) is a protein phosphatase that plays a crucial role in innate immunity. This phosphatase inactivates ERK1/2, which are involved in two opposite functional activities of the macrophage, namely proliferation and activation. Here we found that although macrophage proliferation and activation induce MKP-1 with different kinetics, gene expression is mediated by the proximal promoter sequences localized between À380 and À180 bp. Mutagenesis experiments of the proximal element determined that CRE/AP-1 is required for LPS-or M-CSF-induced activation of the MKP-1 gene. Moreover, the results from gel shift analysis and chromatin immunoprecipitation indicated that c-Jun and CREB bind to the CRE/AP-1 box. The distinct kinetics shown by M-CSF and LPS correlates with the induction of JNK and c-jun, as well as the requirement for Raf-1. The signal transduction pathways that activate the induction of MKP-1 correlate kinetically with induction by M-CSF and LPS.Key words: Activation . Kinases . Macrophage . Phosphatases . Proliferation IntroductionMacrophages perform critical functions during the immune response. These cells are regulators of homeostasis and play an important role in innate and acquired immunity during infection, tumor growth, and wound healing [1]. In response to needs, tissue macrophages proliferate, further differentiate to more specialized macrophagic populations, or become activated. Macrophages, like many other cells of the immune system, are produced in large excess and most undergo apoptosis [2].In the presence of M-CSF, macrophages differentiate and proliferate. However, the proliferation of these cells is blocked when they are activated by Gram-negative LPS or by . Activation causes many biochemical, morphological and functional modifications. Macrophage response to M-CSF and LPS involves the phosphorylation of the three members of the MAPK family [4].MAPK are critical components of signal transduction pathways activated by a range of stimuli and they mediate a number of physiological and pathological changes in cell function [5,6]. MAPK activation requires phosphorylation on a threonine and tyrosine residue located in the activation loop. This process is reversible even in the continued presence of activating stimuli, thereby indicating that protein phosphatases regulate MAPK [7]. Although MAPK are conserved evolutionary pathways present in eukaryotic cells, the kinetics of activation and their subcellular compartmentalization are cell type-specific, and they orchestrate differential cellular responses. For example, in neuronal cells, sustained MAPK phosphorylation of even days is required for cellular activation or differentiation, while in fibroblasts, phosphorylation of this kinase family is very short. In contrast, to Immunol. 2009. 39: 1902-1913 Cristina Casals-Casas et al. 1902 achieve proliferation, extended activation of MAPK is required in these cells [6,7]. The correct spatio-temporal regulation of MAPK signalling is crucial in determining cellular responses to g...

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Distinct roles of Jun : Fos and Jun : ATF dimers in oncogenesis

Cited by 419 publications

References 100 publications

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

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

Growth Inhibitory Effect of the Ternary Complex Factor Net on Human Pancreatic Carcinoma Cell Lines

CREB and AP‐1 activation regulates MKP‐1 induction by LPS or M‐CSF and their kinetics correlate with macrophage activation versus proliferation

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