Selective Regulation of c-jun Gene Expression by Mitogen-Activated Protein Kinases via the 12-O-Tetradecanoylphorbol-13-Acetate- Responsive Element and Myocyte Enhancer Factor 2 Binding Sites

Abstract

To further understand how the mitogen-activated protein kinase (MAPK) signaling pathways regulate AP-1 activity, we have elucidated the physiological role of these cascades in the regulation of c-jun gene expression. c-Jun is a crucial component of AP-1 complexes and has been shown in vitro to be a point of integration of numerous signals that can differentially affect its expression as well as its transcriptional activity. Our strategy was based on the use of (i) genetically modified fibroblasts deficient in components of the MAPK cascades and (ii) pharmacological reagents. The results demonstrate that c-Jun NH₂-terminal protein kinase (JNK) is essential for a basal level of c-Jun expression and for c-Jun phosphorylation in response to stress. In addition to JNK, p38 MAPK or ERK1/2 and ERK5 are required for mediating UV radiation- or epidermal growth factor (EGF)-induced c-Jun expression, respectively. Further studies indicate that p38 MAPK inhibits the activation of JNK in response to EGF, causing a down-regulation of c-Jun. Overall, these data provide important insights into the mechanisms that ultimately determine the function of c-Jun as a regulator of cell fate.

ACKNOWLEDGMENTS

We are indebted to Roger Davis and Richard Flavell for kindly providing the jnk^−/− MEFs. We thank Philip Cohen for providing the ERK1/2 inhibitor PD184352 and Eric Olson, Ron Prywes, Christian Widmann, and Alan Whitmarsh for their generosity in providing the GST-MEF2C, MEF2-Luc, MEKK3, and ERK5 constructs, respectively. We thank A. Whitmarsh for critically reviewing the manuscript.

This work was supported in part by the BBSRC, and principally by the AICR, the Royal Society, and a Lister Institute of Preventive Medicine Research Fellowship to C.T.