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.
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.
Murai
Kasumi
K
Cancer Research UK London Research Institute, Lincoln's Inn Fields Laboratories, Transcription Laboratory, London WC2A 3PX, United Kingdom.
Treisman
Richard
R
D016475:3T3 Cells; D000199:Actins / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D018076:DNA, Complementary; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D016296:Mutagenesis; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins; D026362:Serum Response Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D050807:ets-Domain Protein Elk-1; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
D000199:Actins; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; C494112:ELK1 protein, human; C494113:Elk1 protein, mouse; D005656:Fungal Proteins; C052130:GAL4 protein, S cerevisiae; D011518:Proto-Oncogene Proteins; D016760:Proto-Oncogene Proteins c-fos; D011993:Recombinant Fusion Proteins; D029701:Saccharomyces cerevisiae Proteins; D026362:Serum Response Factor; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D050807:ets-Domain Protein Elk-1; C072545:p62TCF protein, human; C489525:p62TCF protein, mouse; D020742:rhoA GTP-Binding Protein