GROWTH FACTORS Elk-1 Pushes SRF Around

Murai and Treisman demonstrate an intriguing mechanism whereby physical interactions between transcription factors can shift the balance between Rho and Ras stimulation of serum response factor (SRF)-regulated gene transcription. SRF, a transcription factor that regulates many immediate-early genes, is itself stimulated by changes in actin dynamics mediated by Rho-family GTPases. However, the expression of some SRF-regulated genes, such as c-fos, is not stimulated by the Rho-actin pathway but is stimulated by Ras signaling through the mitogen-activated protein kinase (MAPK) pathway, which activates the ternary complex factors (TCFs), a family of transcription factors that bind cooperatively with SRF to DNA. Murai and Treisman investigated the role of interactions between SRF and the TCF protein Elk-1 in limiting c-fos sensitivity to RhoA-actin. Using c-fos promoter mutants transfected into NIH 3T3 cells, the authors demonstrated that deleting a TCF-binding site adjacent to the SRF binding site (TCF mutant) rendered transcriptional activation after serum stimulation sensitive to latrunculin, a specific inhibitor of the RhoA-actin pathway. Serum stimulated expression of the TCF construct, but this stimulation was blocked by latrunculin. In the presence of an Elk-1 mutant that interacted with the SRF and bound to the TCF mutant, as shown by gel shift assay, expression from the TCF construct was not inhibited by latrunculin. Using an Elk-1 mutant that bound DNA independently of the SRF, the authors determined that when the B box, a 20-amino acid region that mediates Elk-1 interaction with SRF, was mutated, then latrunculin still inhibited expression from the TCF construct. Although physical interaction of SRF with the Elk-1 B box inhibited Rho-actin stimulation of the SRF, this interaction potentiated transcriptional activation by Elk-1. This suggests that TCF proteins, through direct interaction with the SRF, can modulate the relative sensitivity of target genes to Rho and Ras regulation.

K. Murai, R. Treisman, 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. Mol. Cell. Biol. 22, 7083-7092 (2002). [Abstract] [Full Text]