Net, a new ets transcription factor that is activated by Ras.

Abstract

Ras signaling appears to be mediated in part by transcription factors that belong to the ets gene family. To identify downstream targets for the Ras signal transduction pathway, we have used Ras-transformed mouse fibroblasts to isolate a new member of the ets gene family, net. Net has sequence similarity in three regions with the ets factors Elkl and SAP1, which have been implicated in the serum response of the fos promoter. Net shares various properties with these proteins, including the ability to bind to ets DNA motifs through the Ets domain of the protein and form ternary complexes with the serum response factor SRF on the fos serum response element, SRE. However, Net differs from Elkl and SAP1 in a number of ways. The pattern of net RNA expression in adult mouse tissues is different. Net has negative effects on transcription in a number of assays, unlike Elkl. Strikingly, Ras, Src, and Mos expression switch Net activity to positive. The study of Net should help in understanding the interplay between Net and other members of the Elk subfamily and their contribution to signal transduction through Ras to the nucleus.

Growth Inhibitory Effect of the Ternary Complex Factor Net on Human Pancreatic Carcinoma Cell Lines

“…Net, like other members of TCFs, has three similar domains, A, B and C, respectively involved in DNA binding, interaction with SRF and activation of transcription when phosphorylated by MAPKs (Janknecht et al 1993(Janknecht et al , 1994(Janknecht et al , 1995Hill et al 1995;Whitmarsh et al 1995;Treisman 1996). However, Net is different from other TCFs in its ability to repress transcription of c-fos (Giovane et al 1994;Maira et al 1996;Criqui-Filipe et al 1999;Buchwalter et al 2004Buchwalter et al , 2005, which is correlated with it's two autonomous inhibitory domains, the net inhibitory domain (NID) (Murre et al 1994) and the C-terminal binding protein interaction domain (CID). The CID interacts with the corepressor E1A C-terminal binding protein, and then inhibits transcription through regulating histone deacetylase activity (Maira et al 1996).…”

Insulin activates Stat3 independently of p21ras-ERK and PI-3K signal transduction

“…The activation of p21ras signal transduction by a plethora of stimuli can lead to the phosphorylation of a number of transcription factors. These include: c-Jun (Binetruy et al, 1991;Pulverer et al, 1991), p62 TCF /Elk-1 (Marais et al, 1993), c-ets-1 (Co er et al, 1993;Galang et al, 1994;Giovane et al, 1994), NF-IL6 (Nakajima et al, 1993), c-Fos and c-Myc (Seth et al, 1992).…”

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

“…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.…”

“…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 (Rao and Reddy, 1993) 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).…”