The increased Sprouty4 expression in response to serum is transcriptionally controlled by Specific protein 1

Sprouty proteins control length and intensity of the intracellular signal transduction cascade activated by mitogens in the cellular environment. As part of a negative feedback loop, their expression is supposed to be elevated by the same factors. In this report, Sprouty4 expression in response to serum and the underlying regulatory mechanisms were investigated. We verified that Sprouty4 expression is activated by serum addition in all tested cells independent of their origin. Strict correlation between Sprouty4 protein levels and promoter activity indicates mainly transcriptional regulation of Sprouty4 serum-responsiveness. Induction of the mitogen-activated protein kinase pathway is required for Sprouty4 promoter activation in the presence of serum. Nonetheless, signal transduction via this pathway is not sufficient to fully induce the Sprouty4 promoter. Instead, deletion and mutation analysis identified two annotated Specific protein 1 binding sites as the critical cis-elements responsible for conferring the serum induction of the promoter. Corroborating, repressed Specific protein 1 activity or levels result in constitutive lowered transcriptional activity of the Sprouty4 promoter. These data demonstrate that Specific protein 1 plays a crucial role in the regulation of Sprouty4 in response to serum.