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Stress-Induced Immediate-Early Gene, Egr-1, Involves Activation of P38/JNK1

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Stress-Induced Immediate-Early Gene, Egr-1, Involves Activation of P38/JNK1 Oncogene (1998) 16, 2915 ± 2926 1998 Stockton Press All rights reserved 0950 ± 9232/98 $12.00 http://www.stockton-press.co.uk/onc Stress-induced immediate-early gene, egr-1, involves activation of p38/JNK1 Cheh Peng Lim, Neeraj Jain and Xinmin Cao Signal Transduction Laboratory, Institute of Molecular and Cell Biology, National University of Singapore, Singapore 117609 The Ras/Raf/MAP kinase (ERK) pathway is a major expression of immediate-early genes, such as c-fos and signaling pathway induced by growth factors in egr-1, which contain SRE in their promoters (for mammalian cells. Two other types of mammalian MAP review see Treisman, 1995). kinases, JNK (SAPK) and p38 (RK, CSBP), are induced Two new types of mammalian MAP kinases which by environmental stress. Although the immediate-early are activated by environmental stress and pro- gene, egr-1, is induced by growth factors, cytokines, in¯ammatory cytokines were recently identi®ed. The dierentiation signals and DNA damaging agents, less is c-Jun NH2-terminal kinase (JNK) group of MAP known about its induction by environmental stress and kinases, also known as stress-activated protein kinases the mechanism involved. Here we report that in NIH3T3 (SAPKs), have been shown to be activated by cells, egr-1 is induced by various stress treatments such interleukin-1 (IL-1), tumor necrosis factor (TNF) and as heat shock, sodium arsenite, ultraviolet (U.V.) U.V. radiation (Kyriakis et al., 1994; De rijard et al., radiation, and anisomycin. p38 and JNK1, but not 1994). JNK binds to the amino terminus of c-jun and ERK2, were activated by these stress treatments. phosphorylates it on serine residues 63 and 73 (Hibi et Induction of egr-1 by anisomycin is inhibited by a al., 1993). The third group of MAP kinases, p38, is speci®c inhibitor of p38, SB 203580. We also show that activated in murine cells by endotoxic lipopolysacchar- p38 and JNK1 activated by their upstream kinases ide (LPS) or hyperosmolarity (Han et al., 1994). induce egr-1 promoter activity through activation of the Homologs of p38 MAP kinase in human cells ternary complex factor, Elk-1. The stress treatments also (CSBP) and Xenopus oocytes (Mpk2) have also been lead to an increase in Egr-1 protein phosphorylation and identi®ed (Lee et al., 1994; Rouse et al., 1994) which its DNA binding activity. Together, our data suggest are very similar to the osmosensing MAPK, HOG1, in that induction of egr-1 gene by growth factors and stress yeast. The p38 kinase was also independently puri®ed are mediated through dierent subgroups of MAP by two groups as reactivating kinase (RK) in sodium kinases which may also dierentially aect egr-1 arsenite-treated PC12 pheochromocytoma cells and function on its target genes. heat-shocked HeLa cells (Rouse et al., 1994), or as a 40 kDa kinase (p40) in IL-1-stimulated KB cells Keywords: egr-1; stress; MAP kinases; p38/JNK1 (Freshney et al., 1994). Although ERKs, JNKs and the p38 kinase family are closely related, they are distinguishable by their speci®c regulatory TXY motif in which X represents glutamic acid in ERKs, proline Introduction in JNKs, and glycine in p38 (De rijard et al., 1994; Payne et al., 1991; Raingeaud et al., 1995). These Activation of receptor tyrosine kinases by binding of kinases are all activated by dual phosphorylation on growth factors to their receptors stimulates prolifera- Thr and Tyr within this motif and each group has both tion and dierentiation in mammalian cells. The unique and overlapping upstream activators and mitogen-activated protein kinase (MAPK) cascade is downstream substrates (Brunet and Pouysse gur, 1996; considered to be a major signaling pathway which Wang and Ron, 1996). links signals from the cell surface to the nuclear The immediate-early gene egr-1 (also known as events in these processes (for review see Hill and NGFI-A, zif268, TIS8 and krox-24) encodes a Treisman, 1995). This signaling pathway involves transcription factor containing a DNA binding transient formation of ras-GTP and activation of raf domain consisting of three zinc ®ngers (Sukhatme et kinase at the membrane, sequential activation of al., 1988; Milbrandt, 1987; Christy and Nathans, MAPK kinase (MAPKK) and MAP kinase 1989b; Lim et al., 1987; Lemaire et al., 1988). The (MAPK)/extracellular signal-regulated protein kinase egr-1 protein (Egr-1) binds to a speci®c GC-rich (ERK) (Marshall, 1994; Leevers et al., 1994; Stokoe sequence in the promoter region of many genes to et al., 1994). ERKs translocate to the nucleus, regulate the expression of these target genes including phosphorylate and thus activate the transcription growth factors and cytokines (Christy and Nathans, factor p62TCF (Shaw et al., 1989), which forms a 1989a; Cao et al., 1993). The egr-1 gene is rapidly and ternary complex with serum response factor (SRF) transiently induced by growth factors and differentia- and serum response element (SRE), and activates the tion signals (Sukhatme et al., 1988; Milbrandt, 1987) and is functionally implicated in cell proliferation and dierentiation processes (Hill and Treisman, 1995; Correspondence: X Cao Sukhatme et al., 1988; Sukhatme, 1990; Nguyen et Received 29 September 1997; revised 7 January 1998; accepted 8 al., 1993). The egr-1 gene has been reported to be January 1998 induced by TNF and IL-1 (Cao et al., 1992a), and Stress-induced egr-1 CP Lim et al 2916 serine/threonine protein phosphatase inhibitor, okadaic Results acid (Herschmann et al., 1989; Cao et al., 1992b), which are known stimulators of p38 and JNK Induction of egr-1 mRNA by stress treatments in (Kyriakis et al., 1994; De rijard et al., 1994; Rouse et NIH3T3 cells al., 1994; Freshney et al., 1994; Cano et al., 1994). In addition, egr-1 is also induced by diverse types of To examine whether egr-1 expression can be induced DNA-damaging agents such as U.V. light (Huang et by various stresses, quiescent NIH3T3 cells were al., 1995), ionizing radiation (Hallahan et al., 1991; treated with heat (428C), anisomycin (25 ng/ml), U.V. Datta et al., 1992), and 1-(b-D-arabinofuranosyl) (40 J/m2), and sodium arsenite (500 mM). Sodium cytosine [(ara-C) Kharbanda et al., 1993]. Since these arsenite mimics the eects of heat shock by inducing DNA-damaging agents also activate JNK (Kharbanda the expression of several heat shock factors (Johnston et al., 1995a,b; Chen et al., 1996) and p38 (Pandey et et al., 1980) and is an activator of p38 (Rouse et al., al., 1996), it is possible that JNK and p38 are involved 1994). Anisomycin, on the other hand, is reported to in the egr-1 induction by these agents. However, less is be an activator of JNKs (Cano et al., 1994). Total known about the egr-1 induction by environmental RNA was isolated and subjected to Northern blot stress and the mechanisms of induction involved. To analysis. A low level of egr-1 mRNA was detectable in investigate the role of egr-1 in the cellular response to the untreated cells (lane 1 in Figure 1a ± d), whereas a stress, we tested the eects of a variety of environ- transient induction of egr-1 mRNA was observed by mental stresses on the egr-1 expression and analysed treatment of these cells with heat shock, anisomycin, or the possible signaling pathways involved. Here, we U.V. The maximum induction of egr-1 transcription report that both the mRNA and protein levels of egr-1 was approximately 33-fold by anisomycin at 30 min are increased after various stress treatments, such as (Figure 1b, lane 3), eightfold by heat shock at 30 min heat shock, sodium arsenite, anisomycin and U.V. (Figure 1a, lane 3) or threefold by U.V. at 60 min radiation in NIH3T3 cells. Our results indicate that (Figure 1c, lane 4), and dropped to the basal level after p38 and JNK, but not ERK2, are involved in the treatment of the cells for 2 h. On the other hand, induction of egr-1 by stress, suggesting that dierent sodium arsenite treatment strongly induced egr-1 MAPK pathways are involved in egr-1 expression expression at 30 min (eightfold) and sustained up to induced by growth factors and stress factors. 4 h (14-fold) as shown in Figure 1d. Induction of egr-1 ab HEAT SHOCK ANISOMYCIN 0 15 30 60 120 240 (min) 0 15 30 60 120 180 (min) egr-1 egr-1 GAPDH GAPDH fold 1 2 8 4 0.5 0.4 fold 1 20.2 33.4 26 0.7 0.2 1 2 3 4 5 6 1 2 3 4 5 6 cd UV ARSENITE 0 15 30 60 120 (min) 0 30 60 120 180 240 (min) egr-1 egr-1 GAPDH GAPDH fold 1 1.1 1.8 2.7 0.1 fold 1 8 10.8 13.6 13.8 14 1 2 3 4 5 1 2 3 4 5 6 Figure 1 Northern blot analysis of egr-1 mRNA induced by various stresses. Quiescent NIH3T3 cells were treated with (a) heat 2 shock (428C), (b) Anisomycin (25 ng/ml), (c) U.V. (40 J/m ), or (d) sodium arsenite (500 mM) for the time periods indicated in minutes (min) on top of each panel. Total RNA was isolated and equal amounts (10 mg) were subjected to Northern blot analysis as described in Materials and methods. egr-1 mRNA is shown in the upper panels. The glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA was used to normalize the amount of RNA loaded and is shown in the lower panels. The numbers at the bottom of each panel indicate the fold of egr-1 induction as compared to control normalized by GAPDH Stress-induced egr-1 CP Lim et al 2917 by dierent doses of sodium arsenite was also protein (indicated by arrows) was detected after 60 min examined and the result showed that the egr-1 mRNA of sodium arsenite treatment which reached a peak at was induced by concentrations as low as 5 mM, 90 min, and decreased after 2 h (Figure 2b).
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