ATF3: A transcription repressor involved in stress responses

Recently, we demonstrated that the liver's response to stress signals entails a cascade of regulation of gene expression. One transcription factor involved in this regulation is the basic region-leucine zipper (bZip) protein, Activating Transcription Factor 3 (ATF3). In contrast to its name, ATF3 is a transcriptional repressor rather than an activator. We discovered that ATF3 is induced in the liver by toxic agents such as acetaminophen, alcohol, and carbon tetrachloride. In addition, ATF3 is induced by stress signals in other tissues such as the heart, brain and kidney. Preliminary results suggest that this induction, at least in part, is due to the activation of ihe stress-inducible JNK/SAPK signal transdtiction pathway. Significantly, the expression of ATF3 correlates with cell injury and cell death. Furthermore, ATF3 is involved in a complicated interplay with another bZip prtoein, gadd153/ChoplO, in the liver upon exposure to stress signals. In light of the correlation between the expression of ATF3 and cell death, we generated transgenic flies that express human ATF3 in various regions of the fly during different stages of fly development using specific GAL4 drivers. Preliminary results indicate that over-expression of ATF3 in early embryonic stages results in a high incidence of embryonic lethality, suggesting that ATF3 may contribute to cell death. Therefore, ATF3 provides a handle to study signal transduction pathways, alteration of gene expression and the molecular basis for cell death induced by stress signals. (This work is supported by an NfH grant given to T. Hai.).