Integration of MAP Kinase Signal Transduction Pathways at the Serum Response Element

Abstract

The ternary complex factor (TCF) subfamily of ETS-domain transcription factors bind with serum response factor (SRF) to the serum response element (SRE) and mediate increased gene expression. The TCF protein Elk-1 is phosphorylated by the JNK and ERK groups of mitogen-activated protein (MAP) kinases causing increased DNA binding, ternary complex formation, and transcriptional activation. Activated SRE-dependent gene expression is induced by JNK in cells treated with interleukin-1 and by ERK after treatment with phorbol ester. The Elk-1 transcription factor therefore integrates MAP kinase signaling pathways in vivo to coordinate biological responses to different extracellular stimuli.

Suppression of c-Fos gene transcription with malignant transformation of human bronchial epithelial cells

“…The activity of the SRE in the c-fos promoter is controlled by ERK-and JNK-dependent pathways, which can either activate or suppress c-fos promoter activity (Marais et al, 1993;whitmarsh et al, 1995;Janknecht and Hunter, 1997;Cavigelli et al, 1995;Gille et al, 1995;Galvin and Shi, 1997;Zinck et al, 1993). We examined the role of these pathways in the regulation of c-fos promoter activity in normal HBE and tumorigenic 1170I cells by transiently co-transfecting fos-LUC and expression vectors containing constitutively active mutant JNK kinase (SEK)-1, MEK-1, or dominant negative mutant JNK kinase kinase (MEKK)-1 cDNAs.…”

“…Ternary complex transcriptional activity is activated by mitogen activated protein (MAP) kinases, including the p42 and p44 (extracellular signal-regulated kinase; ERK) kinases, the cJun N-terminal kinases (JNK)/SAP kinases, and the p38 kinase (Karin, 1995;Marshall, 1995). MAP kinase pathway activation phosphorylates Elk-1, leading to increased Elk-1 DNA binding, ternary complex formation, and activation of the c-fos promoter (Marais et al, 1993;Whitmarsh et al, 1995;Janknecht and Hunter, 1997;Cavigelli et al, 1995;Gille et al, 1995). Binding of the ternary complex to the SRE can stimulate or inhibit c-fos promoter activity, depending on the composition and phosphorylation state of the ternary complex (Galvin and Shi, 1997;Zinck et al, 1993).…”

Signalling of the Ret receptor tyrosine kinase through the c-Jun NH2-terminal protein kinases (JNKs): evidence for a divergence of the ERKs and JNKs pathways induced by Ret

“…On the other side, the two principal isoforms of JNKs, JNK1 and JNK2, were identi®ed by their ability to bind and phosphorylate the amino-terminal (serines 63 and 73) domain of c-Jun (Hibi et al, 1993;Minden et al, 1994;Kyriakis et al, 1994;Derijard et al, 1994). Moreover, activated JNKs are able to phosphorylate at least two other transcription factors, such as ATF-2 (Gupta et al, 1995) and Elk-1 (Whitmarsh et al, 1995). S63/73-phosphorylated c-Jun has potent AP-1 activity and can control the expression of a number of genes, including c-jun itself.…”

Induction of apoptosis by Elk-1 and ΔElk-1 proteins

“…Elk-1, SAP1, and NET/ ERP/SAP2/Elk-3 (Rao et al, 1989;Hipskind et al, 1991;Giovane et al, 1994;Lopez et al, 1994;Dalton and Treisman, 1992;Price et al, 1995;Nozaki et al, 1996). The Elk-1 gene codes for at least two alternately spliced products Elk-1 (Rao et al, 1989) and DElk-1 which function as transcriptional activators (Rao and Reddy, 1992;Bhattacharya et al, 1993), are substrates for MAP kinases Marias et al, 1993;Hill et al, 1993) and JNK protein kinases (Gupta et al, 1996;Whitmarsh et al, 1995). As mentioned earlier, the Elk-1 protein is a TCF which in association with serum response factor (SRF) forms a ternary complex on the serum response element (SRE) of the c-fos promoter and regulates cfos transcription (Hipskind et al, 1991).…”

“…The TCF's which includes Elk-1 have three domains with similar sequences and functions. The ets domain mediates DNA binding, the SRF interaction domain interacts with SRF to form a ternary complex with the c-fos SRE and the C-terminal domain activates transcription upon phosphorylation by MAP kinases (Rao et al, 1989;Rao and Reddy, 1992;Dalton and Treisman, 1992;Janknecht et al, 1993Janknecht et al, , 1994Marias et al, 1993;Giovane et al, 1994;Hipskind et al, 1994;Kortenjann et al, 1994;Lopez et al, 1994;Hill et al, 1995;Price et al, 1995;Whitmarsh et al, 1995) and JNK kinases (Gupta et al, 1996). Thus Elk-1 represents a key link between signal transduction and induction of gene transcription.…”