The activating transcription factor 2: an influencer of cancer progression

Abstract

In contrast to the continuous increase in survival rates for many cancer entities, colorectal cancer (CRC) and pancreatic cancer are predicted to be ranked among the top 3 cancer-related deaths in the European Union by 2025. Especially, fighting metastasis still constitutes an obstacle to be overcome in CRC and pancreatic cancer. As described by Fearon and Vogelstein, the development of CRC is based on sequential mutations leading to the activation of proto-oncogenes and the inactivation of tumour suppressor genes. In pancreatic cancer, genetic alterations also attribute to tumour development and progression. Recent findings have identified new potentially important transcription factors in CRC, among those the activating transcription factor 2 (ATF2). ATF2 is a basic leucine zipper protein and is involved in physiological and developmental processes, as well as in tumorigenesis. The mutation burden of ATF2 in CRC and pancreatic cancer is rather negligible; however, previous studies in other tumours indicated that ATF2 expression level and subcellular localisation impact tumour progression and patient prognosis. In a tissue- and stimulus-dependent manner, ATF2 is activated by upstream kinases, dimerises and induces target gene expression. Dependent on its dimerisation partner, ATF2 homodimers or heterodimers bind to cAMP-response elements or activator protein 1 consensus motifs. Pioneering work has been performed in melanoma in which the dual role of ATF2 is best understood. Even though there is increasing interest in ATF2 recently, only little is known about its involvement in CRC and pancreatic cancer. In this review, we summarise the current understanding of the underestimated ‘cancer gene chameleon’ ATF2 in apoptosis, epithelial-to-mesenchymal transition and microRNA regulation and highlight its functions in CRC and pancreatic cancer. We further provide a novel ATF2 3D structure with key phosphorylation sites and an updated overview of all so-far available mouse models to study ATF2 in vivo.

Combined De-Repression of Chemoresistance Associated Mitogen-Activated Protein Kinase 14 and Activating Transcription Factor 2 by Loss of microRNA-622 in Hepatocellular Carcinoma

“…The MAPK14-ATF2-axis was functionally shown to represent a collateral pathway ensuring persisting ERK-activation in the presence of sorafenib-mediated RAF-inhibition, thereby driving drug resistance [ 11 ]. Therefore, combined de-repression of both MAPK14 and ATF2 as mediated by loss of miR-622 could mechanistically contribute to stronger activation of the beneficial MAPK14-ATF2-axis as compared with alternative pathways of ATF2-activation: ATF2 consists of multiple domains; the most prominent are the N-terminally located transactivation domain, the zinc finger, the bZIP domain and the nuclear localization and nuclear export signals [ 40 ]. Likewise, ATF2 can be phosphorylated by numerous kinases including MAPK14, ERK, PKC, JNK and also by ATM at different sites.…”

ATF2-Induced lncRNA GAS8-AS1 Promotes Autophagy of Thyroid Cancer Cells by Targeting the miR-187-3p/ATG5 and miR-1343-3p/ATG7 Axes

“…ATF2 is a member of the activator protein 1 (AP-1) TF family of the basic leucine zipper (bZIP)-containing DNA-binding proteins and plays crucial roles in cellular development and survival. 43 As a TF, ATF2 regulates miR-132 and miR-320a transcription by binding to their promoters. 44 , 45 However, it has not been reported whether ATF2 can activate lncRNA transcription by binding to the lncRNA promoter.…”

The interplay between ATF2 and NEAT1 contributes to lung adenocarcinoma progression

“…Studies have shown that ATF2 acts as an oncogene via promoting target genes transcription in many cancers [ 5 ]. Moreover, ATF2 is reported to be involved in the crosstalk between paraspeckles and mitochondrial signaling [ 30 ].…”

“…ATF2 is activated by JNK, p38 (MAPK14) and ERK1 through Thr69 and Thr71-phosphorylation, then translocates into the nucleus and thus activates target genes transcription [ 4 ]. The activation of ATF2 promotes the expression of a series of target genes, which refer to cell cycle, immune and inflammatory responses and apoptosis regulation [ 5 ]. However, phosphorylated ATF2 at Thr52 by PKCε binds to the IFNβ1 promoter and represses gene transcription, indicating an transcription suppressor role of ATF2 [ 6 ].…”