Rev7/MAD2B Links c-Jun N-Terminal Protein Kinase Pathway Signaling to Activation of the Transcription Factor Elk-1

Abstract

The mitogen-activated protein (MAP) kinases represent one of the most important classes of signaling cascades that are used by eukaryotic cells to sense extracellular signals. One of the major responses to these cascades is a change in cellular gene expression profiles mediated through the direct targeting of transcriptional regulators, such as the transcription factor Elk-1. Here we have identified human Rev7 (hRev7)/MAD2B/MAD2L2 as an interaction partner for Elk-1 and demonstrate that hRev7 acts to promote Elk-1 phosphorylation by the c-Jun N-terminal protein kinase (JNK) MAP kinases. As phosphorylation of Elk-1 potentiates the activity of its transcriptional activation domain, hRev7 therefore contributes to the upregulation of Elk-1 target genes, such as egr-1, following exposure of cells to stress conditions caused by DNA-damaging agents. Thus, given its previous roles in permitting DNA damage bypass during replication and regulating cell cycle progression, our data linking hRev7 to gene expression changes suggest that hRev7 has a widespread role in coordinating the cellular response to DNA damage.

We thank Anne Clancy for excellent technical assistance; Cathy Tournier and Alan Whitmarsh and members of our laboratory for comments on the manuscript and stimulating discussions; and Ian Stratford, Yoshiki Murakumo, Richard Treisman, Alan Whitmarsh, and Katja Wassmann for reagents.

This work was supported by grants from the Wellcome Trust.