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Mol. Cell. Biol. 22 (20): 7083-7092

Copyright © 2002 by the American Society for Microbiology. All rights reserved.

Interaction of Serum Response Factor (SRF) with the Elk-1 B Box Inhibits RhoA-Actin Signaling to SRF and Potentiates Transcriptional Activation by Elk-1

Kasumi Murai{dagger} and Richard Treisman*

Cancer Research UK London Research Institute, Lincoln's Inn Fields Laboratories, Transcription Laboratory, London WC2A 3PX, United Kingdom

Received for publication 17 May 2002. Revision received 19 June 2002. Accepted for publication 10 July 2002.

Abstract: Serum response factor (SRF) is a transcription factor which regulates many immediate-early genes. Rho GTPases regulate SRF activity through changes in actin dynamics, but some SRF target genes, such as c-fos, are insensitive to this pathway. At the c-fos promoter, SRF recruits members of the ternary complex factor (TCF) family of Ets domain proteins through interactions with the TCF B-box region. Analysis of c-fos promoter mutations demonstrates that the TCF and ATF/AP1 sites adjoining the SRF binding site inhibit activation of the promoter by RhoA-actin signaling. The presence of the TCF binding site is sufficient for inhibition, and experiments with an altered-specificity Elk-1 derivative demonstrate that inhibition can be mediated by the Elk-1 TCF. Using Elk-1 fusion proteins that can bind DNA autonomously, we show that inhibition of RhoA-actin signaling requires physical interaction between the Elk-1 B box and SRF. These results account for the insensitivity of c-fos to RhoA-actin signaling. Interaction of the B box with SRF also potentiates transcriptional activation by the Elk-1 C-terminal activation domain. Combinatorial interactions between SRF and TCF proteins are thus likely to play an important role in determining the relative sensitivity of SRF target genes to Ras- and Rho-controlled signal transduction pathways.

* Corresponding author. Mailing address: Cancer Research UK London Research Institute, Lincoln's Inn Fields Laboratories, Transcription Laboratory, Room 401, 44 Lincoln's Inn Fields, London WC2A 3PX, United Kingdom. Phone: (44) 20-7269-3271. Fax: (44) 20-7269-3093. E-mail: Richard.Treisman{at}cancer.org.uk.

{dagger} Present address: Weatherall Institute, John Radcliffe Hospital, Headington, Oxford OX3 9DS, United Kingdom.

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