Inhibition of c-Jun/ATF2 Phosphorylation, Transrepression of c-Jun/c-Fos : Two Modes of Regulation of the Transcription Factor AP-1 Activity by Glucocorticoid Receptor

Abstract

Changes in the environment lead to the activation of multi-component signaling networks. The intracellular Mitogen-Activated Protein Kinase (MAPK) signaling cascades transfer the signal from the cell membrane to the nucleus, leading to the regulation of gene expression. Expression of genes in response to the signaling is mediated through the activation of transcription factors, such as Activator Protein 1 (AP-1). AP-1 is a family of transcription factors made of different dimers from Jun, Fos and ATF families of proteins. Different AP-1 dimers, such as c-Jun/c-Fos and c-Jun/ATF2 regulate different subset of target genes whose products regulate different aspects of cell function like proliferation, inflammation or cell death. c-Jun/c-Fos and c-Jun/ATF2 are activated by different mechanisms. For example the activation of the Erk MAPK cascade leads to an increase in the expression of Fos, and consequently to an activation of c-Jun/c-Fos. The activation of JNK cascade induces the phosphorylation of c-Jun and ATF2 leading to an increased activity of c-Jun/ATF2. The function of c-Jun/c-Fos and c-Jun/ATF2, in order to prevent the overexpression of the target genes which might lead to pathological changes, must be negatively regulated. One mechanism of negative regulation is the transrepression of AP-1 by the Glucocorticoid receptor (GR). Previous results show that in transrepression GR is recruited to the promoter bound c-Jun/c-Fos through an interaction with nTrip6, a nuclear isoform of the LIM domain protein Trip6. This interaction is essential for transrepression. Results presented in this work show that the transcriptional activity of c-Jun/ATF2 is not regulated by GR in this manner. Indeed, c-Jun/ATF2 does not interact with nTrip6, and is not transrepressed by GR. However, GR represses c-Jun/ATF2 function by inhibiting the JNK-mediated phosphorylation of c-Jun. An increased activity of AP-1, through expression of its target genes can lead to pathological conditions, like a sustained inflammation. Two mechanisms of AP-1 repression by GR can act in concert to block the overexpression of AP-1 target genes, consequently preventing an excessive inflammatory response.