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Molecular and Cellular Biology, December 2004, p. 10340-10351, Vol. 24, No. 23
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.23.10340-10351.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

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

Elaine R. Vickers, Aneta Kasza, Isil Aksan Kurnaz,{dagger} Anne Seifert, Leo A. H. Zeef, Amanda O'Donnell, Andy Hayes, and Andrew D. Sharrocks*

Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom

Received 30 June 2004/ Returned for modification 19 August 2004/ Accepted 3 September 2004

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.

* Corresponding author. Mailing address: Faculty of Life Sciences, University of Manchester, Michael Smith Building, Oxford Rd., Manchester M13 9PT, United Kingdom. Phone: 0044-161-275-5979. Fax: 0044-161-275-5082. E-mail: a.d.sharrocks{at}man.ac.uk.

{dagger} Present address: Department of Genetics and Bioengineering, Faculty of Engineering and Architecture, Yeditepe University, Kayisdagi, Istanbul, Turkey.

Molecular and Cellular Biology, December 2004, p. 10340-10351, Vol. 24, No. 23
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.23.10340-10351.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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