Involvement of transcriptional repressor ATF3 in acceleration of caspase protease activation during DNA damaging agent‐induced apoptosis

Abstract

DNA topoisomerase inhibitors are effective chemotherapeutic agents on several solid tumor cells. They induce a specific signaling cascade that executes an active cell death process (apoptosis), including caspase activation, and the blockage of the signaling is associated with drug-resistance of tumor cells. However, little is known about the initial signal transduction induced by the agents. In the present study, we screened genes that are initially upregulated in caspase-independent manner. We found that the activating transcription factor 3 (ATF3) protein, a repressor of cyclic-AMP responsive element (CRE)-dependent transcription, was strongly induced among CRE-BP/ATF members and subsequently accumulated in nuclei following camptothecin or etoposide treatment. During induction of apoptosis, the accumulation and the nuclear translocation of ATF3 coincided with the activation of caspase protease and were not inhibited by the broad caspase inhibitor Z-VAD-fmk, indicating that ATF3 induction is not a downstream event of caspase activation. When stably or transiently overexpressed, ATF3 markedly accelerated the drug-induced apoptosis and enhanced caspase protease activation. ATF3 strongly downregulated CRE-dependent transcription, while ATF3 did not affect the expression levels of Bcl-2, Bcl-x, or Bax. Our present results indicate that ATF3 plays a critical role in accelerating caspase protease activation and apoptosis. Since CRE-dependent transcription functions as cell survival signaling, ATF3 could control the upstream signaling of apoptosis by repressing CRE-dependent gene expression of cell survival factors.

Identification of ATF-3, caveolin-1, DLC-1, and NM23-H2 as putative antitumorigenic, progesterone-regulated genes for ovarian cancer cells by gene profiling

“…It is a stress-inducible transcriptional repressor that is upregulated in response to many physiological stress signals (Hai et al, 1999;Hai and Hartman, 2001). ATF-3 has been shown to be a downstream regulator of the Jun NH(2)-terminal kinase (JNK)-mediated stress kinase signaling pathway (Liang et al, 1996), which is associated with activation of caspases (Mashima et al, 2001). In the present study, ATF-3 expression was markedly reduced in OVCA cells compared to HOSE cells but could be restored by P4 treatment in OCa cells.…”

“…The proapoptotic action of ATF-3 has been demonstrated in other types of cancer cell. For example, treatment of Hela S3 and HT 1080 with chemotherapeutic agents induced concomitant upregulation of ATF-3 and activation of caspases (Mashima et al, 2001). Yet, we were the first to show that ATF-3 is proapoptotic in normal and malignant OSE cells, and that the expression of this gene is under P4 regulation.…”

ATF3 induction following DNA damage is regulated by distinct signaling pathways and over-expression of ATF3 protein suppresses cells growth

“…Several lines of evidence indicate that ATF3 is involved in homeostasis, wound healing, metastasis and the signaling pathways mediating cellular response to genotoxic stress (Allen-Jennings et al, 2001;Hai and Hartman, 2001;Ishiguro and Nagawa, 2000;Wolfgang et al, 1997Wolfgang et al, , 2000. In addition, ATF3 is demonstrated to accelerate caspase protease activation during DNA damaging agentinduced apoptosis (Mashima et al, 2001). Most recently, ATF3 was found to interact physically with p53 and disrupt the p53-mediated activation of the MMP2 gene, which plays a role in tumor metastases (Yan et al, 2002).…”

“…ATF3 protein is expressed at a low levels in normal and quiescent cells, but can be rapidly and highly induced in response to multiple and diverse extracellular signals including growth factors, cytokines and some genotoxic stress agents Hai and Hartman, 2001;Hai et al, 1999). However, little is known about ATF3 physiological function although several lines of evidence indicate that ATF3 might be involved in homeostasis, wound healing, cell adhesion, cancer cell invasion, apoptosis and signaling pathways (Allen-Jennings et al, 2001;Chen et al, 1996;Hai and Hartman, 2001;Ishiguro and Nagawa, 2000;Mashima et al, 2001;Wolfgang et al, 1997Wolfgang et al, , 2000. Recently, ATF3 was reported to interact with p53 and antagonize its trans-activations of the MMP2 gene, which is involved in the process of promoting tumor metastases (Yan et al, 2002).…”

Gene Modulation by the Cyclooxygenase Inhibitor, Sulindac Sulfide, in Human Colorectal Carcinoma Cells

“…ATF3 is also a transcription factor that forms heterodimers with C/EBP␤ regulating the expression of Gadd153 and several other growth-regulating cellular promoters and even heterodimerizes with Gadd153, resulting in down-regulation of ATF3 and C/EBP␤-mediated gene regulation (51). ATF3 is induced by camptothecin and etoposide, agents known to induce apoptosis (44,52,53). Furthermore, ATF3, which is highly expressed after sulindac sulfide treatments, may play an important role in sulindac sulfide-induced apoptosis and antitumorigenic activity.…”