Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

ATF3 Activating Transcription Factor 3

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_612

Synonyms

Historical Background

The term ATF was first used in 1987 to refer to a putative polypeptide with the activity to bind to the sites on the adenovirus E2, E3, and E4 promoters with sequences similar to the consensus TGACGT(C/A)(G/A) (Lee et al. 1987). However, it was later found that, instead of a single polypeptide, many polypeptides can bind to the sequence (Hai et al. 1988; Raychaudhuri et al. 1987). Cloning of the corresponding cDNAs using the consensus sequence to screen the expression library revealed seven different clones (Hai et al. 1989). These proteins were collectively called the ATF family of proteins. Over the years, identical or homologous cDNA clones have been isolated, expanding the size of this protein family (for previous reviews, see Hai and Hartman 2001; Hai et al. 1999). Because the consensus ATF binding site is the same as the cAMP responsive element (CRE) (Montminy and Bilezsikjian 1987) and because ATF1 is 75% similar to the CRE-binding protein ( CREB) at the amino acid level (Hai et al. 1989), sometimes the ATF and  CREB proteins are referred to as the ATF/ CREB or  CREB/ATF family of proteins. ATF3 is a member of this family.

DNA Binding by ATF3

Both ATF and  CREB proteins bind to DNA using their basic region/leucine zipper (bZip) motif and belong to a superfamily of bZip proteins that includes ATF,  CREB, AP1 (Fos/Jun), C/EBP, and Maf families (see Hai 2006 for a dendrogram). These proteins can form cross-family heterodimers. In addition, many of these proteins can bind to each other’s consensus sequences (which are similar to each other) or the composite sites (a previous review, Hai and Hartman 2001). Thus, their names reflect the history of discovery, rather than the differences (or similarities) between them. An unbiased way to view them is that they all belong to a superfamily of bZip transcription factors that form homodimers and selective heterodimers, with potentially overlapping DNA-binding sequences (for a few reviews on bZip proteins, see Amoutzias et al. 2007; Hurst 1995; Newman and Keating 2003; Vinson et al. 2002). Strictly speaking, there is no such site as the “ATF3 consensus binding sequence,” since any sites bound by ATF3 are likely to be also recognized by other bZip proteins. When searching for potential ATF3 binding sites on a given promoter, one should scan the sequence not just for the consensus ATF sequence, but also the AP1 sequence (TGACTCA, one nucleotide deletion from the ATF site), and sequences with several deviations from either consensus. If potential sites are identified, it is necessary to test the binding experimentally. If no potential sites are identified, it does not necessarily mean that ATF3 does not regulate the promoters. It is possible that ATF3 can bind to the promoters at yet unidentified sites, or ATF3 can be recruited to these promoters via other proteins. Alternatively, ATF3 may regulate them indirectly via regulating other transcription factors that in turn regulate the promoters of interest. For more discussions on DNA binding by ATF3, see McConoughey et al. (2011).

Transcriptional Activity and Target Promoters of ATF3

Although the name “ATF” implies that the proteins are transcriptional activators, it is clear now that ATF3 can be an activator or repressor, depending on the promoter or cellular context (previous reviews, Hai 2006; Hai and Hartman 2001). Over the years, many potential ATF3 target genes (direct or indirect) have been identified. Table 1 lists some of the potential direct target genes that fulfill minimally two criteria: (a) ATF3 was shown to be recruited to their promoters in vivo by chromatin-immunoprecipitation (ChIP) assay; (b) their steady-state mRNA or protein levels are affected by ectopic expression or knockdown of ATF3. Note that changes in steady-state mRNA level could be due to change in transcription, or mRNA stability, or both, and the change in the steady-state protein level could be due to regulation at various steps. Thus, the second criterion by itself does not necessarily mean transcriptional regulation. In addition, it does not mean that the influence of ATF3 on the genes is direct or indirect. However, combined with the first criterion (recruitment of ATF3 to their promoters in vivo), it suggests that ATF3 may, at least in part, regulate their transcription. For some of the target genes listed in Table 1, ATF3 was shown to modulate their transcription in vivo by the indicated assay: pol II occupancy on the promoters/genes or the measurement of their pre-mRNA levels. Results based on transient transfection coupled with reporter assay were not included as evidence for in vivo transcription, because the assay does not address the issue of endogenous gene regulation. In addition, in vitro DNA binding (such as DNase footprint or electrophoretic mobility shift assay) were not included as evidence for ATF3 binding to the promoters. For potential ATF3 target genes identified using less stringent criteria, see McConoughey et al. (2011).
ATF3 Activating Transcription Factor 3, Table 1

Potential target genes of ATF3

Genea

Cellsb used in the indicated assays

Effect of ATF3

References

ChIP

Western or RT-PCR

Transcription assays

Pre-mRNAa or PolIIb

AdipoR1

HepG2

HepG2, MIN6N8, and C2C12

ND4

Repression

(Amoutzias et al. 2007)

AdipoR2

HepG2

 

ND

Repression

(Demidova et al. 2009)

bNIP3

INS-1

Mouse primary islets

ND

Activation

(Gilchrist et al. 2006)

Cdc25A

HCT116

HCT116

ND

Repression

(Hai 2006)

CCL2

INS-1

Mouse primary islets

ND

Activation

(Gilchrist et al. 2006)

CCL4

RAW264.7

Mouse peritoneal and bone marrow derived macrophages

ND

Repression

(Hai and Hartman 2001)

Cyclin D1

MEFs

Ras-transformed MEFs

MEFsa

Repression

(Hai et al. 1988)

FN-1

MCF10CA1a

MCF10CA1a

MCF10CA1ab

Activation

(Hai et al. 1989)

GLUT4

HEK293T

Mouse white adipose tissue

ND

Repression

(Hai et al. 1999)

HIF-2α

HeLa

MEFs

ND

Activation

(Hai et al. 2010)

IFN-γ

Mouse NK cells

Mouse NK cells

ND

Repression

(Ho et al. 2008)

IL-1β

INS-1

Mouse primary islets

ND

Activation

(Gilchrist et al. 2006)

IL-6

RAW264.7

RAW264.7

ND

Repression

(Hurst 1995)

INS-1

Mouse primary islets

ND

Activation

(Gilchrist et al. 2006)

IL-12b

RAW264.7

RAW264.7

ND

Repression

(Hurst 1995)

IRS2

MIN6 and INS823/13

MIN6 and INS823/13

INS823/13b

Repression

(Kang et al. 2003)

MMP1

Primary mouse monocytes

THP-1

ND

Repression

(Khuu et al. 2007)

MMP13

MDA-MB231

MDA-MB231

ND

Activation

(Kim et al. 2009)

Noxa

INS-1

INS-1

ND

Activation

(Gilchrist et al. 2006)

p15PAF

HaCaT

MEFs

ND

Activation

(Kim et al. 2010)

Slug

MCF10CA1a

MCF10CA1a

MCF10CA1ab

Activation

(Hai et al. 1989)

Snail

MCF10CA1a

MCF10CA1a

MCF10CA1ab

Activation

(Hai et al. 1989)

STAT1

MIN6N8

MIN6N8

ND

Activation

(Koh et al. 2010)

TNFα

RAW264.7

RAW264.7

ND

Repression

(Korb et al. 2008)

INS-1

Mouse primary islets

ND

Activation

(Gilchrist et al. 2006)

TWIST1

MCF10CA1a

MCF10CA1a

MCF10CA1ab

Activation

(Hai et al. 1989)

aGene: AdipoR1 adiponectin receptor 1, AdipoR2 adiponectin receptor 2, bNIP3 Bcl-2/E1B-19 K-interacting protein 3, Cdc25A Cdc25 protein phosphastase type A, CCL Chemokine (CC motif) ligand, FN-1 Fibronectin, GLUT4 glucose transporter 4, HIF-2α hypoxia-inducible factor 2 alpha subunit, IFN-γ interferon-γ, IL interleukin, IRS2 insulin receptor substrate 2, MMP matrix metalloproteinase, Noxa Latin for damage, p15 PAF proliferating Cell Nuclear Antigen-associated factor KIAA0101, STAT signal transducer and activator of transcription, TNF-α tumor necrosis factor

bCells: C2C12 mouse myoblast cell line, HaCaT human skin keratinocyte cell line, HCT116 human colon carcinoma cell line, HEK293T human embryonic kidney cell line, HeLa human cervical cancer cell line, HepG2 human liver carcinoma cell line, INS-1 rat insulinoma cell line, INS823/13 rat insulinoma cell line derived from INS-1, MCF10CA1a human breast cancer cell line, MDA-MB231 human breast cancer cell line, MEFs immortalized mouse embryonic fibroblasts, MIN6 mouse pancreatic β cell line, MIN6N8 mouse pancreatic β cell line, RAW264.7 mouse leukemic monocyte macrophage cell line, THP-1 human acute monocytic leukemia cell l

Biological Function of ATF3

ATF3 as a “Hub”

Overwhelming evidence indicates that the ATF3 mRNA level is low in many cell lines and tissues, but upregulated by a variety of signals, usually within 2 h of induction (see Hai (2006) for a short list, and see McConoughey et al. (2011) for more). One striking feature of ATF3 induction is that it is neither stimulus- nor cell type-specific. This lack of specificity raises an important question: What is the purpose of inducing ATF3? Previously, the idea that ATF3 is a hub of the cellular adaptive-response network to respond to signals perturbing homeostasis was put forth (Hai et al. 2010). This idea was based on the following observations (Amoutzias et al. 2007). A broad spectrum of stimuli can induce ATF3 (above) (Demidova et al. 2009). A variety of signaling pathways have been shown to induce ATF3, such as the JNK, Erk, p38, PKC, and NFκB pathways. This is consistent with the numerous binding sites on the ATF3 promoters (ATF3 has at least two promoters, see a review, (Hai et al. 2010) that are recognized by transcription factors targeted by the above signaling pathways. (Gilchrist et al. 2006) Analysis of the amino acid sequence of ATF3 revealed many potential posttranslational modification sites, again supporting the idea that ATF3 is a target for regulation by many signaling pathways. For detailed description and references, see Hai et al. (2010).

Additional observations to support the “hub” idea came from bioinformatics analysis. Using the Cytoscape program, Aderem and colleagues analyzed the known transcription factor protein–protein interaction network and found ATF3 to interact with a number of transcription factors, including AP1, CHOP, NFκB, and  p53 (Gilchrist et al. 2006). As shown in Fig. 1, an expansion of this analysis to include all proteins – not just transcription factors – using the Ingenuity Pathway Analysis database revealed that ATF3 interacts with many proteins, further supporting the idea of ATF3 as a hub.
ATF3 Activating Transcription Factor 3, Fig. 1

Potential ATF3 interacting proteins

Figure 1 shows the potential ATF3-interacting proteins derived from the Ingenuity Pathway Analysis database. The level of evidence for their interaction varies, depending on the assays used in the studies. To address whether any interaction occurs in vivo in specific cell types, it is important to examine it using appropriate assays. White rectangle in the figure denotes classically defined sequence-specific transcription factors; blue circle denotes cofactors or regulators that modulate transcription factors; yellow diamond denotes other types of proteins.

Abbreviations used in Fig. 1 are the following. AP1: Activator protein 1; ATF: Activating Transcription Factor; BATF3: Basic leucine zipper transcription factor, ATF-like 3; C1orf103: Chromosome 1 open reading frame 103; CEBPG: CCAAT/enhancer binding protein gamma; CHOP: C/EBP homologous protein; CREB5:Cyclic AMP-responsive element-binding protein 5; CREBBP: CREB-binding protein; EP300: E1A binding protein p300; FGFR3: Fibroblast growth factor receptor 3; FHL2: Four and a half LIM domain protein 2; FOS: FBJ murine osteosarcoma viral oncogene homolog; HDAC1: Histone Deacetylase 1; ID3: Inhibitor of DNA-binding 3; IGSF21: Immunoglobin superfamily 21; JUN: Jun proto-oncogene; MDM2: Murine double minute oncogene; NFE2L2: Nuclear factor (erythroid-derived 2)-like 2: NFkB: Nuclear Factor-KappaB; NUF2: NDC80 kinectochore complex component; POLR3D: Polymerase (RNA) III (DNA directed) polypeptide D; RELA: v-rel reticuloendotheliosis viral oncogene homolog A (avian); RIF1: RAP1 interacting factor 1; SMAD3: Mothers against decapentaplegic homolog 3; SS18L1: Synovial sarcoma translocation gene on chromosome 18 like protein 1; TP53: Tumor protein 53; ZNF212: Zinc finger protein 212

ATF3 as a Cell–Cell Communication Gene

By its nature as an immediate-early gene, ATF3 has far-reaching effects. Immediate-early genes encode transcription factors and are known to turn on/off genes encoding transcription factors, which in turn regulate downstream genes, leading to a cascade of changes in transcriptional programs. Thus, to understand ATF3 function, an important task is to elucidate its target genes – either direct or indirect targets. Table 1 lists some genes that are likely to be direct targets (see above for criteria for inclusion). However, ATF3 has been shown to affect the expression of many more genes (see previous reviews, Hai et al. 2010; McConoughey et al. 2011; Thompson et al. 2009). Due to the lack of evidence for ATF3 recruitment to their promoters in vivo, it is not clear whether they are direct or indirect target genes of ATF3. Among the diversity of ATF3 targets, some can be grouped into functional pathways or groups. (a) ATF3 modulates the expression of numerous inflammatory genes – not only in immune cells (such as macrophages, mast cells, and T cells) but also in non-immune cells (see database (Korb et al. 2008) and a previous review Hai et al. 2010). (b) ATF3 functions as a co-transcription factor for Smad3 to regulate many TGFβ target genes, such as those that affect cell motility and cell cycle (Kang et al. 2003; Yin et al. 2008; Yin et al. 2010). Furthermore, ATF3 forms a positive feedback loop on TGFβ: ATF3 gene is induced by TGFβ (Kang et al. 2003) and its gene product upregulates the expression of TGFβ gene (Yin et al. 2010). Thus, ATF3 appears to play an important role in TGFβ signaling.

TGFβ and the inflammatory gene products (such as cytokines and chemokines) are all soluble factors. This, combined with the “hub” idea above, supports the following view of ATF3. Upon the disturbance of homeostasis by extra- or/and intra-cellular signals, one of the key genes that the cells turn on is ATF3. After induction, ATF3 initiates a cascade of changes in gene expression with a key consequence of releasing various soluble factors, which in turn disturb the homeostasis of the cells receiving the signals. Thus, ATF3 is a key molecule for cell–cell communication, both as a gene to respond to the signals and as a gene to send out signals for communication. This proposed view of ATF3 is supported by a recent cRNA microarray data that cell–cell communication is within the top ten functional groups of genes regulated by ATF3 (Wolford et al. in preparation).

Other Functions

The above two proposed functions of ATF3 are based on literature with a perspective of viewing ATF3 from a broad angle. They are not meant to be comprehensive and do not include the function of ATF3 in various cellular processes, such as apoptosis, cell cycle, cell motility, metabolism, and DNA repair. For those functions, see previous reviews (Hai et al. 2010; McConoughey et al. 2011; Thompson et al. 2009). In this context, two points relevant to the understanding of ATF3 functions are of interest.
  1. (a)

    Although ATF3 is a transcription factor, its subcellular localization is not limited to the nucleus. MacLeod and colleagues reported low levels of cytoplasmic ATF3 (in addition to nuclear ATF3) in human breast tumor samples by immunohistochemistry (Wang et al. 2008). Similar cytoplasmic localization of ATF3 has also been observed by other investigators (not published). The subcellular localization of ATF3 is likely a regulated event, as suggested by the observation that ATF3 localizes in the cytoplasm of Stat1 knockdown hepatocytes but in the nucleus of the control knockdown cells (Kim et al. 2009). These are potentially interesting observations. As shown in the literature, some proteins have unexpected functions outside their originally identified subcellular location, such as the mitochondrial function of the transcription factor  p53 (a review, Vaseva and Moll 2009) and the nuclear function of the cytoplasmic membrane protein epidermal growth factor receptor (EGFR, Liccardi et al. (2011) and references therein). Clearly, further analysis for the subcellular localization of ATF3 is required. It is intriguing that FGFR3 – a cytoplasmic membrane receptor – is a potential ATF3-interacting protein based on a yeast two-hybrid screen (Stelzl et al. 2005). If this interaction can be validated in mammalian cells, it would be important to address the subcellular localization of their interaction (nuclear or non-nuclear) and the functional consequences.

     
  2. (b)

    Several isoforms of ATF3 have been identified (a review, McConoughey et al. 2011). However, the functional importance of these isoforms and the regulation of their expression are not well understood. When investigating ATF3 functions, this is an area to consider.

     

Potential Roles of ATF3 in the Pathogenesis of Diseases

Inflammation: A Potential Unifying Component for the Roles of ATF3 in Various Diseases

As detailed in a previous review (Hai et al. 2010), ATF3 modulates the expression of many inflammatory genes. Work by several groups clearly identified ATF3 to play a role in modulating inflammatory responses in macrophages (Gilchrist et al. 2006; Khuu et al. 2007; Whitmore et al. 2007). Furthermore, using systems biology approach combined with genome-wide ChIP-on-chip analyses, Aderem and colleagues identified a large array of ATF3 target genes (not just inflammatory genes) in macrophages and generated an interactive database (Korb et al. 2008). In addition to macrophages, ATF3 also regulates inflammatory genes in other immune cells (such as CD4+-T cells, natural killer cells, mast cells, and dendritic cells) and nonimmune cells (such as fibroblasts and epithelial cells). See Table 2 in Hai et al. (2010) for a list and references. Considering the importance of inflammation in the pathogenesis of various diseases, it is reasonable to speculate that the ability of ATF3 to modulate inflammatory response genes – either in the immune cells or nonimmune cells – plays a key role in its potential implication in various diseases [for more discussions, see Hai et al. (2010)]. Below is a brief review of the data for ATF3 in cancer.

ATF3 in Cancer

Various mouse models have been used to investigate the potential roles of ATF3 in the pathogenesis of diseases. These include transgenic mice ectopically expressing ATF3 in selective tissues, knockout mice deficient in ATF3, and orthotopic injection of cells with modulation of ATF3 levels. See Table 3 in a previous review (Hai et al. 2010) for a brief description of the mouse models and phenotypes. Taking this set of literature together with the in vitro data that ATF3 affects many cellular processes relevant to cancer development (such as apoptosis, cell cycle progression, angiogenesis; for a review, see McConoughey et al. (2011)), it is reasonable to conclude that ATF3 most likely plays a role in the pathogenesis of cancer. However, ATF3 does not simply inhibit or promote cancer; rather, its function varies depending on the cellular context. As shown in the literature, ATF3 can either inhibit or enhance processes such as apoptosis, cell cycle progression, and tumor formation. Since these reports were derived from vastly different cell lines or models with different contexts (see McConoughey et al. (2011) for some examples), one idea is that the role of ATF3 is affected by cellular context. To address what specific features of the cells may affect the roles of ATF3 in cancer development, one study utilized isogenic cell lines. These cells share the same genetic background except the genetic and/or epigenetic alterations that allow them to have varying degrees of malignancy. Interestingly, ATF3 enhances apoptosis in normal or untransformed epithelial cells but has an opposite effect on a malignant cell line derived from them (Yin et al. 2008). Thus, ATF3 plays a dichotomous role, depending on the degree of malignancy of the cells. This concept explains the phenotypes of many transgenic mice models ectopically expressing ATF3 in selective tissues (see Table 3 in Hai et al. (2010) for specifics). In general, ATF3 has deleterious effects on the corresponding tissues, since the cells are untransformed. An exception is the CK5-ATF3 transgenic mice (which express ATF3 in the basal epithelial cells by the bovine cytokeratin promoter 5); the mice developed mammary carcinoma in biparous mice (Wang et al. 2007; Wang et al. 2008). Presumably, after cycles of proliferation and apoptosis, the mammary epithelial cells in biparous mice develop cellular context allowing ATF3 to be “co-opted” and become pro-oncogenic.

All the above data are derived from cell lines in culture dish or mouse models; a critical question is whether the conclusion that ATF3 affects cancer development can be extrapolated to human. At present, ATF3 has been detected in various tumors, such as breast, prostate, squamous cell carcinoma, and Hodgkin lymphoma (see Table 4 in Hai et al. (2010)). Due to its nature of induction by various stress signals, it is not surprising that ATF3 is expressed within the tumors. The question is whether this has any functional relevance. Does ATF3 play a causal or preventive role? Can its expression be used as a predictive marker (positive or negative) for clinical outcomes? Since ATF3 can be induced in different cell types by various signals, it is likely to be expressed in both cancer epithelial cells and stromal cells. Does its expression in stromal cells have any functional relevance? Considering the complexity of ATF3 biology, these are challenging questions and much work is required to address them.

Summary

ATF3 is a member of the bZip superfamily of transcription factors. This review puts forth two potential functions of ATF3 from a broad perspective. (a) ATF3 as a hub: Overwhelming evidence indicates that ATF3 is induced by a variety of extra- and intra-cellular signals. This, combined with other clues (such as the involvement of various signaling pathways in its induction and its interaction with many proteins), prompted the proposal that ATF3 functions as a “hub” of the cellular adaptive-response network to respond to signals perturbing homeostasis. (b) ATF3 in cell–cell communication: Since ATF3 is a transcription factor, it exerts its actions at least in part by regulating downstream target genes. Analyses of its target genes – either direct or indirect targets – revealed that a consequence of inducing ATF3 is to turn on a variety of genes encoding soluble factors, which in turn disturbs the homeostasis of the cells receiving the signals. Thus, ATF3 is a key molecule for cell–cell communication, both as a gene to respond to the signals and as a gene to send out signals for communication. Various mouse models have been used to investigate the potential roles of ATF3 in the pathogenesis of diseases. A previous review put forth the idea that the ability of ATF3 to modulate inflammatory response genes is a key component for the potential implication of ATF3 in various diseases. This review highlights the evidence and clues that ATF3 most likely plays a role in the pathogenesis of cancer – in a context-dependent manner, not simply anti- or pro-cancer. A critical question is whether the findings from cell culture and mouse models can be extrapolated to human. This is a challenging question; in addressing this issue, it is important to consider the complexity of ATF3 biology.

References

  1. Amoutzias GD, Veron AS, Weiner 3rd J, Robinson-Rechavi M, Bornberg-Bauer E, Oliver SG, Robertson DL. One billion years of bZIP transcription factor evolution: conservation and change in dimerization and DNA-binding site specificity. Mol Biol Evol. 2007;24:827–35.CrossRefPubMedGoogle Scholar
  2. Demidova AR, Aau MY, Zhuang L, Yu Q. Dual regulation of Cdc25A by Chk1 and p53-ATF3 in DNA replication checkpoint control. J Biol Chem. 2009;284:4132–9.CrossRefPubMedGoogle Scholar
  3. Gilchrist M, Thorsson V, Li B, Rust AG, Korb M, Kennedy K, Hai T, Bolouri H, Aderem A. Systems biology approaches identify ATF3 as a negative regulator of toll-like receptor 4. Nature. 2006;441:173–8.CrossRefPubMedGoogle Scholar
  4. Hai T. The ATF transcription factors in cellular adaptive responses. In: Ma J, editor. Gene expression and regulation. Beijing/New York: Higher Education Press/Springer; 2006. p. 322–33.Google Scholar
  5. Hai T, Hartman MG. The molecular biology and nomenclature of the ATF/CREB family of transcription factors: ATF proteins and homeostasis. Gene. 2001;273:1–11.CrossRefPubMedGoogle Scholar
  6. Hai T, Liu F, Allegretto EA, Karin M, Green MR. A family of immunologically related transcription factors that includes multiple forms of ATF and AP-1. Genes Dev. 1988;2:1216–26.CrossRefPubMedGoogle Scholar
  7. Hai T, Liu F, Coukos WJ, Green MR. Transcription factor ATF cDNA clones: an extensive family of leucine zipper proteins able to selectively form DNA-binding heterodimers. Genes Dev. 1989;3:2083–90.CrossRefPubMedGoogle Scholar
  8. Hai T, Wolfgang CD, Marsee DK, Allen AE, Sivaprasad U. ATF3 and stress responses. Gene Expr. 1999;7:321–35.PubMedGoogle Scholar
  9. Hai T, Wolford CC, Chang YS. ATF3, a hub of the cellular adaptive-response network, in the pathogenesis of diseases: is modulation of inflammation a unifying component? Gene Expr. 2010;15:1–11.CrossRefPubMedGoogle Scholar
  10. Ho HH, Antoniv TT, Ji JD, Ivashkiv LB. Lipopolysaccharide-induced expression of matrix metalloproteinases in human monocytes is suppressed by IFN-gamma via superinduction of ATF-3 and suppression of AP-1. J Immunol. 2008;181:5089–97.PubMedCentralCrossRefPubMedGoogle Scholar
  11. Hurst HC. Transcription factors 1: bZIP proteins. Protein Profile. 1995;2:101–68.PubMedGoogle Scholar
  12. Kang Y, Chen CR, Massague J. A self-enabling TGFβ response coupled to stress signaling: Smad engages stress response factor ATF3 for Id1 repression in epithelial cells. Mol Cell. 2003;11:915–26.CrossRefPubMedGoogle Scholar
  13. Khuu CH, Barrozo RM, Hai T, Weinstein SL. Activating transcription factor 3 (ATF3) represses the expression of CCL4 in murine macrophages. Mol Immunol. 2007;44:1598–605.CrossRefPubMedGoogle Scholar
  14. Kim JY, Lee SH, Song EH, Park YM, Lim JY, Kim DJ, Choi KH, Park SI, Gao B, Kim WH. A critical role of STAT1 in streptozotocin-induced diabetic liver injury in mice: controlled by ATF3. Cell Signal. 2009;21:1758–67.PubMedCentralCrossRefPubMedGoogle Scholar
  15. Kim JY, Song EH, Lee S, Lim JH, Choi JS, Koh IU, Song J, Kim WH. The induction of STAT1 gene by activating transcription factor 3 contributes to pancreatic beta-cell apoptosis and its dysfunction in streptozotocin-treated mice. Cell Signal. 2010;22:1669–80.CrossRefPubMedGoogle Scholar
  16. Koh IU, Lim JH, Joe MK, Kim WH, Jung MH, Yoon JB, Song J. AdipoR2 is transcriptionally regulated by ER stress-inducible ATF3 in HepG2 human hepatocyte cells. FEBS J. 2010;277:2304–17.CrossRefPubMedGoogle Scholar
  17. Korb M, Rust AG, Thorsson V, Battail C, Li B, Hwang D, Kennedy KA, Roach JC, Rosenberger CM, Gilchrist M, Zak D, Johnson C, Marzolf B, Aderem A, Shmulevich I, Bolouri H. The innate immune database (IIDB). BMC Immunol. 2008;9:7.PubMedCentralCrossRefPubMedGoogle Scholar
  18. Lee KAW, Hai TY, SivaRaman L, Thimmappaya B, Hurst HC, Jones NC, Green MR. A cellular protein, activating transcription factor, activates transcription of multiple E1a-inducible adenovirus early promoters. Proc Natl Acad Sci U S A. 1987;84:8355–9.PubMedCentralCrossRefPubMedGoogle Scholar
  19. Liccardi G, Hartley JA, Hochhauser D. EGFR nuclear translocation modulates DNA repair following cisplatin and ionizing radiation treatment. Cancer Res. 2011;71:1103–14.PubMedCentralCrossRefPubMedGoogle Scholar
  20. McConoughey SJ, Wolford CC, Hai T. Activating transcription factor 3, UCSD-signaling molecule pages. 2011. http://www.signaling-gateway.org/molecule/search?nm=ATF3.
  21. Montminy MR, Bilezsikjian LM. Binding of a nuclear protein to the cyclic AMP response element of the somatostatin gene. Nature. 1987;328:175–8.CrossRefPubMedGoogle Scholar
  22. Newman JRS, Keating AE. Comprehensive identification of human bZIP interactions with coiled-coil arrays. Science. 2003;300:2097–101.CrossRefPubMedGoogle Scholar
  23. Raychaudhuri P, Rooney R, Nevins JR. Identification of an E1A-inducible cellular factor that interacts with regulatory sequences within the adenovirus E4 promoter. EMBO J. 1987;6:4073–81.PubMedCentralPubMedGoogle Scholar
  24. Stelzl U, Worm U, Lalowski M, Haenig C, Brembeck FH, Goehler H, Stroedicke M, Zenkner M, Schoenherr A, Koeppen S, Timm J, Mintzlaff S, Abraham C, Bock N, Kietzmann S, Goedde A, Toksoz E, Droege A, Krobitsch S, Korn B, Birchmeier W, Lehrach H, Wanker EE. A human protein-protein interaction network: a resource for annotating the proteome. Cell. 2005;122:957–68.CrossRefPubMedGoogle Scholar
  25. Thompson MR, Xu D, Williams BR. ATF3 transcription factor and its emerging roles in immunity and cancer. J Mol Med. 2009;87:1053–60.PubMedCentralCrossRefPubMedGoogle Scholar
  26. Vaseva AV, Moll UM. The mitochondrial p53 pathway. Biochim Biophys Acta. 2009;1787:414–20.CrossRefPubMedGoogle Scholar
  27. Vinson C, Myakishev M, Acharya A, Mir AA, Moll JR, Bonovich M. Classification of human B-ZIP proteins based on dimerization properties. Mol Cell Biol. 2002;22:6321–35.PubMedCentralCrossRefPubMedGoogle Scholar
  28. Wang A, Arantes S, Conti C, McArthur M, Aldaz CM, MacLeod MC. Epidermal hyperplasia and oral carcinoma in mice overexpressing the transcription factor ATF3 in basal epithelial cells. Mol Carcinog. 2007;46:476–87.CrossRefPubMedGoogle Scholar
  29. Wang A, Arantes S, Yan L, Kiguchi K, McArthur MJ, Sahin A, Thames HD, Aldaz CM, Macleod MC. The transcription factor ATF3 acts as an oncogene in mouse mammary tumorigenesis. BMC Cancer. 2008;8:268.PubMedCentralCrossRefPubMedGoogle Scholar
  30. Whitmore MM, Iparraguirre A, Kubelka L, Weninger W, Hai T, Williams BR. Negative regulation of TLR-signaling pathways by activating transcription factor-3. J Immunol. 2007;179:3622–30.CrossRefPubMedGoogle Scholar
  31. Yin X, DeWille J, Hai T. A potential dichotomous role of ATF3, an adaptive-response gene, in cancer development. Oncogene. 2008;27:2118–27.CrossRefPubMedGoogle Scholar
  32. Yin X, Wolford CC, McConoughey SJ, Ramsey SA, Aderem A, Hai T. ATF3, an adaptive-response gene, enhances TGFβ signaling and cancer initiating cell features in breast cancer cells. J Cell Sci. 2010;123:3558–65.PubMedCentralCrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of Molecular and Cellular Biochemistry, Center for Molecular NeurobiologyOhio State Biochemistry Program Ohio State UniversityColumbusUSA
  2. 2.Department of Biomedical Informatics, OSUCCC Biomedical Informatics Shared ResourcesOhio State UniversityColumbusUSA
  3. 3.Molecular and Cellular BiochemistryOhio State UniversityColumbusUSA