EGF stimulates gastrin promoter through activation of Sp1 kinase activity

Abstract

Epidermal growth factor (EGF) receptor activation stimulates gastrin gene expression through a GC-rich element called gastrin EGF response element (gERE). This element is bound by Sp1 family members and is a target of the ras-extracellular signal-regulated kinase (Erk) signal transduction cascade. This raised the possibility that Sp1 may be phosphorylated by kinases of this signaling pathway. Erk is capable of phosphorylating other mitogen-inducible transcription factors, e.g., Elk and Sap, suggesting that Erk may also mediate EGF-dependent phosphorylation of Sp1. This possibility was tested by studying Sp1-dependent kinase activity in extracts prepared from EGF-activated AGS cells by use of solid-phase kinase assays and immunoprecipitation of metabolically labeled Sp1. The results revealed that Sp1 kinase activity (like gastrin promoter activation) is inhibited by PD-98059 and, therefore, is dependent on mitogen-activated protein kinase kinase 1 (Mek 1). However, EGF-dependent activation of endogenous Erk did not account for most of the Sp1 kinase activity, since Erk and additional Sp1 kinase activity analyzed in a solid-phase kinase assay eluted from an ion-exchange column in different fractions. Phosphoamino acid analysis of in vivo radiolabeled Sp1 demonstrated that the kinase phosphorylates Sp1 on Ser and Thr in response to EGF. Therefore, most EGF-stimulated Sp1 kinase activity is Mek 1 dependent and distinct from Erk.

v-Src-mediated Down-regulation of SSeCKS Metastasis Suppressor Gene Promoter by the Recruitment of HDAC1 into a USF1-Sp1-Sp3 Complex

“…For example, the activation of the ERK MAPK by growth factors is known to induce Sp1 phosphorylation, correlating with increased DNA binding activity (55,56). Other modifications such as acetylation occur in cancer cells,(reviewed in Ref.…”

Oxidative Stress Regulates Vascular Endothelial Growth Factor-A Gene Transcription through Sp1- and Sp3-dependent Activation of Two Proximal GC-rich Promoter Elements

“…In addition, current studies demonstrated that Sp1 also participates in the regulation of inducible gene expression and that interaction of Sp1 with other transcription factors and/or cofactors such as CREB-binding protein, p300, or CRSP 84 may represent an important transcriptional control mechanism (43). More recently, it became clear that Sp1 can also be regulated through changes of its phosphorylation state (44), and subsequently, different signaling pathways including Rasdependent activation of the MEK1/ERK cascade have been identified to target Sp1 (45)(46)(47). Similar to Sp1, Sp3 represents a zinc finger transcription factor comprising highly conserved DNA-binding domains, but analysis of their functional properties revealed significant differences between these two proteins (42,43).…”

Activation of Extracellular Signal-Regulated Kinase Signaling by Epidermal Growth Factor Mediates c-Jun Activation and p300 Recruitment in Keratin 16 Gene Expression

“…It has been reported that p42/p44 MAPK directly phosphorylates Sp1 on threonines 453 and 739 both in vitro and in vivo and then increases Sp1 binding activity and transcriptional efficiency of the vascular endothelial growth factor promoter in a derivative of fibroblasts stably expressing an estrodiol-inducible Raf-1 (Milanini et al, 2002). Moreover, EGF stimulates gastrin promoter through the activation of Sp1 kinase activity (Chupreta et al, 2000). EGF-stimulated apoA-I gene expression is mediated solely through the Ras-MAPK cascade, and enhanced activity of this pathway requires Sp1 with an intact phosphorylation site at Thr266 in human hepatoma (Zheng et al, 2001).…”