Ternary Complex Factor-Serum Response Factor Complex-Regulated Gene Activity Is Required for Cellular Proliferation and Inhibition of Apoptotic Cell Death

Abstract

Members of the ternary complex factor (TCF) subfamily of the ETS-domain transcription factors are activated through phosphorylation by mitogen-activated protein kinases (MAPKs) in response to a variety of mitogenic and stress stimuli. The TCFs bind and activate serum response elements (SREs) in the promoters of target genes in a ternary complex with a second transcription factor, serum response factor (SRF). The association of TCFs with SREs within immediate-early gene promoters is suggestive of a role for the ternary TCF-SRF complex in promoting cell cycle entry and proliferation in response to mitogenic signaling. Here we have investigated the downstream gene regulatory and phenotypic effects of inhibiting the activity of genes regulated by TCFs by expressing a dominantly acting repressive form of the TCF, Elk-1. Inhibition of ternary complex activity leads to the downregulation of several immediate-early genes. Furthermore, blocking TCF-mediated gene expression leads to growth arrest and triggers apoptosis. By using mutant Elk-1 alleles, we demonstrated that these effects are via an SRF-dependent mechanism. The antiapoptotic gene Mcl-1 is identified as a key target for the TCF-SRF complex in this system. Thus, our data confirm a role for TCF-SRF-regulated gene activity in regulating proliferation and provide further evidence to indicate a role in protecting cells from apoptotic cell death.

We thank Linda Shore and Anne Clancy for excellent technical support and Mike Jackson for help with the FACS analysis. We also thank Richard Treisman, Steve Edwards, and Xiaodong Wang for reagents, Caroline Dive for helpful advice, and Shen-Hsi Yang, Paul Shore, and Alan Whitmarsh for comments on the manuscript.

This work was funded by grants from the Wellcome Trust (WT), the AICR, and Cancer Research UK. E.R.V. was supported by a William Ross CRC studentship. A.K. was supported by the WT and Foundation for Polish Science Fellowship. A.D.S. was supported by a Research Fellowship from the Lister Institute of Preventive Medicine.