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.

SummaryThe activating transcription factor 3 (ATF3) gene is induced by a variety of signals, including many of those encountered by cancer cells. We present evidence that ATF3 is induced by TGF in the MCF10CA1a breast cancer cells and plays an integral role for TGF to upregulate its target genes snail, slug and twist, and to enhance cell motility. Furthermore, ATF3 upregulates the expression of the TGFb gene itself, forming a positive-feedback loop for TGF signaling. Functionally, ectopic expression of ATF3 leads to morphological changes and alterations of markers consistent with epithelial-to-mesenchymal transition (EMT). It also leads to features associated with breast-cancer-initiating cells: increased CD24 low -CD44 high population of cells, mammosphere formation and tumorigenesis. Conversely, knockdown of ATF3 reduces EMT, CD24 low -CD44 high cells and mammosphere formation. Importantly, knocking down twist, a downstream target, reduces the ability of ATF3 to enhance mammosphere formation, indicating the functional significance of twist in ATF3 action. To our knowledge, this is the first report demonstrating the ability of ATF3 to enhance breast cancer-initiating cell features and to feedback on TGF. Because ATF3 is an adaptive-response gene and is induced by various stromal signals, these findings have significant implications for how the tumor microenvironment might affect cancer development.

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OBJECTIVE-␤-Cell failure is an essential component of all types of diabetes, and the insulin receptor substrate 2 (IRS2) branch of signaling plays a key role in ␤-cell survival and function. We tested the hypothesis that activating transcription factor 3 (ATF3), a stress-inducible proapoptotic gene, downregulates the expression of IRS2 in ␤-cells.RESEARCH DESIGN AND METHODS-We used both the gain-and loss-of-function approaches to test the effects of ATF3 on IRS2 gene expression. We also analyzed the binding of ATF3 to the IRS2 promoter by chromatin immunoprecipitation assay and the transcription of the IRS2 gene by polymerase II occupancy assay. Furthermore, we tested the ability of IRS2 to alleviate the proapoptotic effects of ATF3 in cultured ␤-cells and in transgenic mice using the rat insulin promoter to drive the transgenes. CONCLUSIONS-IRS2 is a target gene of ATF3, and its repression by ATF3 contributes, at least partly, to the apoptosis induced by ATF3. Because ATF3 is a stress-inducible gene, our work provides a direct link to explain how environmental stress factors can modulate IRS2 gene transcription. Diabetes 57: 635-644, 2008 I nsulin signaling plays an important role in the pathogenesis of diabetes. Upon activation, the insulin receptor recruits and phosphorylates its substrates, insulin receptor substrates (IRSs), to initiate signal transduction (rev. in 1 and 2). Although the IRS family of proteins includes IRS1-IRS6 and other proteins such as GAB1, GAB2, and CBL (2,3), the majority of the insulin action appears to be mediated by IRS1 and IRS2 (rev. in 3). Research using mice deficient in IRS1 or IRS2 has shed light on their respective roles in diabetes. Mice deficient in IRS1 develop peripheral insulin resistance and mild glucose intolerance but never develop diabetes, presumably due to the compensation by the increased pancreatic ␤-cell growth and insulin secretion (4,5). In contrast, mice deficient in IRS2 consistently develop diabetes (6,7). While insulin resistant at an early age, the IRS2 Ϫ/Ϫ mice are initially able to compensate for this through increased insulin secretion. However, as they age, their ␤-cells fail to adequately compensate for insulin demand and begin to die, thus resulting in overt diabetes. This progression from insulin resistance to ␤-cell failure and finally diabetes mimics the natural development of type 2 diabetes. Thus, the IRS2 branch of signaling is a key pathway that regulates both the peripheral insulin signaling and ␤-cell mass/ function (rev. in 8). Significantly, the diabetic phenotype in the IRS2 knockout mice can be prevented by crossing them with transgenic mice expressing IRS2 in their ␤-cells (9) or transgenic mice engineered to have increased ␤-cell mass and function by either expression of Pdx1 (10) or haploinsufficiency of FoxO1 (11). RESULTS-ExpressionDespite the above results from animal models indicating a potential role of IRS2 in type 2 diabetes, polymorphisms in IRS2 gene are rare and not associated with common type 2 diabetes in humans (12; rev...