ATF3, a hub of the cellular adaptive-response network, in the pathogenesis of diseases: is modulation of inflammation a unifying component?

Abstract

Activating transcription factor 3 (ATF3) gene encodes a member of the ATF family of transcription factors and is induced by various stress signals. All members of this family share the basic region-leucine zipper (bZip) DNA binding motif and bind to the consensus sequence TGACGTCA in vitro. Previous reviews and an Internet source have covered the following topics: the nomenclature of ATF proteins, the history of their discovery, the potential interplays between ATFs and other bZip proteins, ATF3-interacting proteins, ATF3 target genes, and the emerging roles of ATF3 in cancer and immunity (see footnote 1). In this review, we present evidence and clues that prompted us to put forth the idea that ATF3 functions as a "hub" of the cellular adaptive-response network. We will then focus on the roles of ATF3 in modulating inflammatory response. Inflammation is increasingly recognized to play an important role for the development of many diseases. Putting this in the context of the hub idea, we propose that modulation of inflammation by ATF3 is a unifying theme for the potential involvement of ATF3 in various diseases.

Figure 1

ATF3 as a hub of the cellular adaptive-response network. (A) Various signaling pathways were linked to ATF3 induction by gain-of-function or loss-of-function approach, or both. Numbers in parentheses indicate the references. Due to space limitations, the citation is not comprehensive and we apologize to those whose work is not cited here. LPS, lipopolysaccharide. (B) Analyses of the two kb region of the most proximal promoter (designated as P2 in Fig. 2) by several programs (Jaspar, MotifMogul, PROMO) (9,12,16) revealed numerous transcription factor binding sites.

Figure 2

A schematic of the mouse ATF3 gene structure. Arrows indicate the transcriptional start site (TSS); open boxes indicate exons and lines between the boxes represent introns. The P1, P2, and a putative promoter are indicated (see text for description). The P2 promoter has multiple start sites, resulting in variable size of exon A2. The end of exon E is indicated by a dotted line, because the transcriptional termination site is not clear. For the purpose of illustration here, it is arbitrarily defined as the point where polyA is added. CpG islands identified by the CpG Island Searcher program (61) is indicated by the gray dotted line. Note that the figure is not proportional to scale and the intron between exons A2 and B is about 5 kb. Met: methionine. *: Termination condon. The human ATF3 gene has similar genomic organization and CpG islands spanning exon A2.