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Signal Transduction and the Ets Family of Transcription Factors Oncogene (2000) 19, 6503 ± 6513 ã 2000 Macmillan Publishers Ltd All rights reserved 0950 ± 9232/00 $15.00 www.nature.com/onc Signal transduction and the Ets family of transcription factors John S Yordy1 and Robin C Muise-Helmericks*,1,2 1Center for Molecular and Structural Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina, SC 29403, USA; 2Department of Cell Biology and Anatomy, Medical University of South Carolina, Charleston, South Carolina, SC 29403, USA Cellular responses to environmental stimuli are con- expression required for cellular growth, dierentiation trolled by a series of signaling cascades that transduce and survival. One group of downstream eectors of extracellular signals from ligand-activated cell surface these signaling pathways is the Ets family of transcrip- receptors to the nucleus. Although most pathways were tion factors. Ets family members can also be initially thought to be linear, it has become apparent that considered upstream eectors of signal transduction there is a dynamic interplay between signaling pathways pathways controlling the expression of a number of that result in the complex pattern of cell-type speci®c signaling components including both receptor tyrosine responses required for proliferation, dierentiation and kinases and intermediate signaling molecules. survival. One group of nuclear eectors of these The Ets family of transcription factors is de®ned by signaling pathways are the Ets family of transcription a conserved winged helix ± turn ± helix DNA binding factors, directing cytoplasmic signals to the control of domain (Papas et al., 1989; Wasylyk et al., 1993; gene expression. This family is de®ned by a highly Werner et al., 1995). Cumulative data have revealed conserved DNA binding domain that binds the core that this family of transcription factors are down- consensus sequence GGAA/T. Signaling pathways such stream eectors of the Ras-MAPK signaling cascades as the MAP kinases, Erk1 and 2, p38 and JNK, the PI3 (Wasylyk et al., 1998). Phosphorylation of Ets factors kinases and Ca2+-speci®c signals activated by growth by MAPKs controls their subsequent downstream factors or cellular stresses, converge on the Ets family of activity, protein partnerships, target speci®city and factors, controlling their activity, protein partnerships transactivation. Two major groups within this family and speci®cation of downstream target genes. Interest- have been extensively studied, the Ets group, including ingly, Ets family members can act as both upstream and Ets1, Ets2 and Pointed, and the ternary complex downstream eectors of signaling pathways. As down- factors (TCFs) which include Elk1, Sap1a, Sap1b, Fli1 stream eectors their activities are directly controlled by and Net. speci®c phosphorylations, resulting in their ability to Ets1, Ets2 and Pointed (Pt2) each contain a C- activate or repress speci®c target genes. As upstream terminal conserved DNA binding domain and an N- eectors they are responsible for the spacial and terminal domain referred to as the Pointed domain. temporal expression or numerous growth factor recep- This group of Ets family members has a single MAPK tors. This review provides a brief survey of what is phosphorylation site located near the Pointed domain known to date about how this family of transcription (Brunner et al., 1994; Wasylyk et al., 1997). TCFs, on factors is regulated by cellular signaling with a special the other hand, contain a transactivation domain that focus on Ras responsive elements (RREs), the MAP can be phosphorylated on multiple serine and kinases (Erks, p38 and JNK) and Ca2+-speci®c pathways threonine residues (Hipskind et al., 1994a; Treisman, and includes a description of the multiple roles of Ets 1994). Phosphorylation generally enhances their ability family members in the lymphoid system. Finally, we will to activate transcription by binding to speci®c discuss other potential mechanisms and pathways sequences termed Ras-responsive elements (RREs) involved in the regulation of this important family of and serum response elements (SREs) present in the transcription factors. Oncogene (2000) 19, 6503 ± 6513. promoters of many immediate early response genes. Although much work has been done to identify the Keywords: Ets; transcription; MAP kinase; Ras; signal relevant members of the major signaling cascades, there transduction is continual identi®cation of potential new members and modes of regulation in these signal transduction networks. While the eort to map these networks and Introduction identify new members continues, many of the major signaling pathways leading to the regulation of Ets A series of signaling pathways, including the MAP family of transcription factors have been described. A kinase (MAPK) pathways ERK1/2, p38 and JNK, as brief review of a portion of the existing literature will well as the PI3 kinase pathway, among others, are be given and used to re¯ect upon some of the general either activated by growth factors or by cellular stress themes understood at this time and possible future such as UV irradiation (Figure 1). These signaling directions of Ets signaling research. pathways transmit external stimuli to the nucleus and activate numerous transcription factors, resulting in both the temporal and spatial changes in gene Ras-responsive elements The ®rst RRE was de®ned within the polyoma virus *Correspondence: RC Muise-Helmericks enhancer and is composed of consensus Ets binding Ets and cellular signaling JS Yordy and RC Muise-Helmericks 6504 Figure 1 Schematic representation of the signaling pathways resulting in the control of Elk1 phosphorylation. For simplicity, although SRF is also regulated via these signaling pathways, the focus of the diagram is the eect on Elk1. Activation of the MAPK pathways Erk1/2, p38 and JNK result in the positive regulation of Elk1. Induction of Ca2+ ¯ux induces both a positive signal, resulting in the activation of Erk1/2 and a negative signal via the phosphatase calcineurin sites (EBS) ¯anking binding sites for AP-1. AP-1 is a transactivation in the absence of MAPK activation heterodimeric transactivating complex whose speci®city (Wasylyk et al., 1990, 1997). results from the dimerization of dierent related Drosophila contains eight Ets-related family members subunits, e.g. c-Fos, c-Jun and is controlled by Ras (Reviewed by Hsu and Schultz, this issue), two of activation (Binetruy et al., 1991; Deng and Karin, which are pointed and yan. Pointed encodes two 1994; Smeal et al., 1991, 1992). Activation of the RRE transcriptional activator proteins, PntP1 and PntP2 within the polyoma enhancer was found to require a (Klambt, 1993; Scholz et al., 1997) while yan,a Ras-dependent activation of both Ets1 and AP1 transcriptional repressor, appears to produce a single activity (Wasylyk et al., 1990). Since this initial protein product (Lai and Rubin, 1992). Of the two description, the transcriptional activation of other proteins encoded by the pointed locus, PntP2 requires genes has also been shown to require RREs. Ras- MAPK phosphorylation to become active (Brunner et stimulated RRE promoter elements are able to activate al., 1994; O'Neill et al., 1994). Multiple roles have been the expression of genes known to be involved in assigned to pointed and yan including the development cellular transformation and migration, including uPA, of the wing, midline glia and retina. An orchestrated stromelysin-1 (MMP-3) and collagenase-1 (MMP-1) balance between PntP2 and Yan is necessary for proper (Aoyama and Klemenz, 1993; Bortner et al., 1993; Drosophila eye development, and both are targets of Chambers and Tuck, 1993; Grant et al., 1995; Wasylyk the Ras-MAPK pathway initiated by Sevenless, a et al., 1991; Wu et al., 1994). Ras-responsiveness can receptor tyrosine kinase (Brunner et al., 1994; Gabay be blocked by dominant-negative members of the AP1 et al., 1996; O'Neill et al., 1994; Rebay and Rubin, and Ets families (Bortner et al., 1993; Galang et al., 1995; Simon et al., 1991). Activation of the Ras- 1994; Gutman and Wasylyk, 1991; Langer et al., 1992; MAPK pathway leads to the phosphorylation of Yan, Lloyd et al., 1991; Wasylyk et al., 1994). Signi®cantly, which is then exported from the nucleus into the dominant-negative Ets proteins inhibit Ras-mediated cytoplasm where it is degraded (Gabay et al., 1996; cellular transformation without inhibiting normal cell Rebay and Rubin, 1995; Rogge et al., 1995). growth in some cell types (Langer et al., 1992; Wasylyk Concurrent with the degradation of Yan, PntP2 is et al., 1994). Ras-MAPK speci®c phosphorylation of phosphorylated by the same signaling cascade, stimu- Ets1 or Ets2 is necessary for the synergistic activation lating its transactivating capacity (O'Neill et al., 1994). of the RRE in conjunction with AP1 and mutations in This allows for the expression of downstream target either threonine 38 in Ets1 or threonine 72 in Ets2 genes necessary for eye development. In parallel with inhibit RRE activation (Yang et al., 1996). However, in the transactivation of RREs by Ets1 and Ets2, PntP2 some cell types Ets1 and Ets2 possess a high level of requires the interaction with the Drosophila jun Oncogene Ets and cellular signaling JS Yordy and RC Muise-Helmericks 6505 homologue, D-jun, for downstream function (Treier et shown to mediate a large number of extracellular al., 1995). signals, including tetradecanoyl phorbol acetate (TPA), Gene expression controlled by RREs has multiple lipopolysaccharide (LPS), serum,
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