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

Abstract

Mammalian cells have a remarkable diverse repertoire of response to genotoxic stress that damage DNA. Cellular responses to DNA damaging agents will initially exhibit gene induction, which is regulated by complex mechanism(s) and probably involves multiple signaling pathways. In this paper, we demonstrate that induction of ATF3 protein, a member of the ATF/CREB family of transcription factors, by ionizing radiation (IR) requires normal cellular p53 function. In contrast, induction of ATF3 after UV radiation (UV) or Methyl methanesulphonate (MMS) is independent of p53 status. Induction of ATF3 by DNA damage is rapid, transient, and through a transcriptional mechanism. The ATF3 promoter is induced by UV and MMS, but not by IR. In addition, ATF3 promoter can be activated by MEKK1, an upstream activator of the ERK and JNK kinase pathway, but not induced following p53 expression. Those results indicate that regulation of ATF3 induction after DNA damage utilizes both the p53-dependent andindependent pathways, and may also involve MAP kinase signaling pathways. Using the tetracyclineinducible system (tet-off), we have found that overexpression of ATF3 protein moderately suppresses cell growth. Interestingly, over-expression of ATF3 protein is able to slow down progression of cells from G1 to S phase, indicating that ATF3 protein might play a negative role in the control of cell cycle progression.

Response of malignant B lymphocytes to ionizing radiation: Gene expression and genotype

“…31,32 Moreover, the observed upregulation of ATF3 is thought to slow down progression from G 1 to S phase but might also be involved in G 2 arrest after IR. 33,34 Furthermore, upregulation of PCNA in Reh cells may enhance DNA replication but was probably a result of IR induced DNA repair in our study. 35 Temporal expression profiles may give information about the onset of gene regulation in relation to when the phenotypic changes are detected.…”

ATF3 Activates Stat3 Phosphorylation through Inhibition of p53 Expression in Skin Cancer Cells

“…ATF3 can be also induced by UV and ionizing irradiation, which was the main environmental causes of skin carcinogenesis (Fan et al, 2002;Kool et al, 2003;Koike et al, 2005). ATF3 has been revealed to enhance keratinocyte tumor formation in mice model (Wu et al, 2010), while how ATF3 promotes skin cancer development remains unclear.…”

“…ATF3 is expressed at low levels in normal cells but can be rapidly induced by multiple and diverse extracellular signals including growth factors, cytokines and some genotoxic stress agents Hai et al, 1999;Hai and Hartman, 2001;Fan et al, 2002;Taketani et al, 2012, Wang et al, 2012Lee et al, 2013). The physiological function of ATF3 has been addressed in several cell lines that ATF3 might be involved in homeostasis, wound healing, cell adhesion, cancer cell invasion, apoptosis and signaling pathways Wolfgang et al, 1997;Wolfgang et al, 2000;Allen-Jennings et al, 2001;Gold et al, 2012;Jang et al, 2012;Rose et al, 2012).…”

“…The physiological function of ATF3 has been addressed in several cell lines that ATF3 might be involved in homeostasis, wound healing, cell adhesion, cancer cell invasion, apoptosis and signaling pathways Wolfgang et al, 1997;Wolfgang et al, 2000;Allen-Jennings et al, 2001;Gold et al, 2012;Jang et al, 2012;Rose et al, 2012). Over-expression of ATF3 protein moderately suppresses cell growth through slowing down progression from G1/S transition in Hela cells (Fan et al, 2002). Conversely, ATF3 promotes growth factor-independent proliferation in chick embryo (Perez et al, 2001) and enhance serum-induced cell proliferation in rat fibroblasts (Tamura et al, 2005).…”

Induction of activating transcription factor 3 by anoxia is independent of p53 and the hypoxic HIF signalling pathway

“…Second, expression of ATF3 has been demonstrated to alter a variety of cellular processes relevant to cancer progression including cell cycle, cell death, angiogenesis and metastasis (Hai and Hartman, 2001;Okamoto et al, 2006). Third, ATF3 expression can be regulated transcriptionally by a variety of signalling pathways or transcription factors, including nuclear factor kappa B (Hartman et al, 2004), EGR-1 (Bottone et al, 2005), by p53-dependent and -independent pathways (Amundson et al, 1999;Fan et al, 2002), and by the c-Jun NH 2 -terminal kinase (JNK) (Cai et al, 2000), which is activated by MKK7 (Tournier et al, 1997). In addition to promoter activation, ATF3 mRNA can also accumulate as a result of mRNA stabilization (Liang et al, 1996).…”