Ternary complex factor-serum response factor complex-regulated gene activity is required for cellular proliferation and inhibition of apoptotic cell death.
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.
Vickers
Elaine R
ER
Faculty of Life Sciences, University of Manchester, Michael Smith Building, Oxford Rd., Manchester M13 9PT, United Kingdom.
Kasza
Aneta
A
Kurnaz
Isil Aksan
IA
Seifert
Anne
A
Zeef
Leo A H
LA
O'donnell
Amanda
A
Hayes
Andy
A
Sharrocks
Andrew D
AD
D000483:Alleles; D017209:Apoptosis; D015152:Blotting, Northern; D015153:Blotting, Western; D001973:Bromodeoxyuridine / Q000494:pharmacology; D002453:Cell Cycle; D002460:Cell Line; D049109:Cell Proliferation; D002469:Cell Separation; D002470:Cell Survival; D047369:Chromatin Immunoprecipitation; D004268:DNA-Binding Proteins / Q000378:metabolism; D015536:Down-Regulation; D005434:Flow Cytometry; D017930:Genes, Reporter; D005822:Genetic Vectors; D006367:HeLa Cells; D006801:Humans; D051821:Lymphoid Enhancer-Binding Factor 1; D008856:Microscopy, Fluorescence; D008934:Mitogens; D008954:Models, Biological; D008958:Models, Molecular; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D017434:Protein Structure, Tertiary; D020133:Reverse Transcriptase Polymerase Chain Reaction; D026362:Serum Response Factor / Q000378:metabolism*; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection
D004268:DNA-Binding Proteins; D051821:Lymphoid Enhancer-Binding Factor 1; D008934:Mitogens; D026362:Serum Response Factor; D014157:Transcription Factors; D001973:Bromodeoxyuridine