Activation of Transcription Factor NF-κB and p38 Mitogen-activated Protein Kinase Is Mediated by Distinct and Separate Stress Effector Pathways

Mitogen-activated protein (MAP) kinases are important mediators of the cellular stress response. Here, we investigated the relationship between activation of the MAP kinase p38 and transcription factor NF-κB. Different forms of cellular stress were found to preferentially trigger either p38 or NF-κB. Arsenite or osmotic stress potently activated p38 but were ineffective in inducing NF-κB activation. Tumor necrosis factor-α and hydrogen peroxide, in contrast, led to NF-κB activation but only modestly stimulated p38. The activation of NF-κB was strongly abolished by antioxidants, while the activity of p38 and transcription factor AP-1 were increased. Inhibition of small GTPases including Rac and Cdc42 prevented p38 and AP-1 activation without interfering with NF-κB. In addition, inhibition of p38 by a pharmacological inhibitor or a dominant-negative mutant of MAP kinase kinase-6, an activator of the p38 pathway, interfered with NF-κB-dependent gene expression but not its DNA binding activity. Our results indicate that activation of p38 and NF-κB are mediated by separate pathways, which may converge further downstream in the cell nucleus. Different forms of cellular stress, however, initially trigger distinct signaling cascades involving either oxidative stress or GTPase-coupled pathways. Mitogen-activated protein (MAP) kinases are important mediators of the cellular stress response. Here, we investigated the relationship between activation of the MAP kinase p38 and transcription factor NF-κB. Different forms of cellular stress were found to preferentially trigger either p38 or NF-κB. Arsenite or osmotic stress potently activated p38 but were ineffective in inducing NF-κB activation. Tumor necrosis factor-α and hydrogen peroxide, in contrast, led to NF-κB activation but only modestly stimulated p38. The activation of NF-κB was strongly abolished by antioxidants, while the activity of p38 and transcription factor AP-1 were increased. Inhibition of small GTPases including Rac and Cdc42 prevented p38 and AP-1 activation without interfering with NF-κB. In addition, inhibition of p38 by a pharmacological inhibitor or a dominant-negative mutant of MAP kinase kinase-6, an activator of the p38 pathway, interfered with NF-κB-dependent gene expression but not its DNA binding activity. Our results indicate that activation of p38 and NF-κB are mediated by separate pathways, which may converge further downstream in the cell nucleus. Different forms of cellular stress, however, initially trigger distinct signaling cascades involving either oxidative stress or GTPase-coupled pathways. Gene induction by cellular stresses is mediated through biochemical processes that mostly involve the interplay of multiple signaling pathways. Depending on the nature of the stimulus, intricate protein kinases are activated that ultimately phosphorylate transcription factors and result in gene expression. Central mediators that propagate signals from the cell membrane to the nucleus are protein kinases related to the mitogen-activated protein (MAP) 1The abbreviations used are: MAP, mitogen-activated protein; ERK, extracellular signal-regulated protein kinase; JNK, c-Jun NH2-terminal kinase; ATF, activating transcription factor; TNF, tumor necrosis factor; ROI, reactive oxygen intermediate; MKK, MAP kinase kinase; GST, glutathioneS-transferase; DTT, dithiothreitol; AP-1, activator protein-1; PMA, phorbolmyristyl acetate; PDTC, pyrrolidine dithiocarbamate; EMSA, electrophoretic mobility shift assay; NF-κB, nuclear factor-κB. kinase superfamily. To date, at least three different subtypes of MAP kinases are known (reviewed in Refs. 1Cahill M.A. Janknecht R. Nordheim A. Curr. Biol. 1996; 6: 16-19Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar, 2Treisman R. Curr. Biol. 1996; 8: 205-215Crossref Scopus (1167) Google Scholar, 3Su B. Karin M. Curr. Opin. Immunol. 1996; 8: 402-411Crossref PubMed Scopus (726) Google Scholar). These are in turn activated by distinct upstream dual specificity kinases thus revealing the existence of protein kinase modules that can be independently and simultaneously activated. Whereas mitogens and growth factors lead to activation of protein kinase cascades resulting in activation of ERK family MAP kinases, many forms of cellular stress preferentially trigger two related signaling pathways (4Minden A. Lin A. Claret F.-X. Abo A. Karin M. Cell. 1995; 81: 1147-1157Abstract Full Text PDF PubMed Scopus (1450) Google Scholar, 5Coso O.A. Chiariello M. Yu J.-C. Teramoto H. Crespo P. Xu N. Miki T. Gutkind J.S. Cell. 1995; 81: 1137-1146Abstract Full Text PDF PubMed Scopus (1574) Google Scholar, 6Galcheva-Gargova Z. Dérijard B. Wu I.H. Davis R.J. Science. 1994; 265: 806-808Crossref PubMed Scopus (539) Google Scholar, 7Kyriakis J.M. Banerjee P. Nikolakaki E. Dai T. Rubie E.A. Ahmad M.F. Avruch J. Woodgett J.R. Nature. 1994; 369: 156-160Crossref PubMed Scopus (2440) Google Scholar, 8Freshney N.W. Rawlinson L. Guesdon F. Jones E. Cowley S. Hsuan J. Saklatvala J. Cell. 1994; 78: 1039-1049Abstract Full Text PDF PubMed Scopus (786) Google Scholar). These center on two MAP kinase homologues called stress-activated protein kinases or Jun NH2-terminal kinases (JNKs), and p38, also termed reactivating kinase. Targets of stress-activated protein kinase and JNK include several transcription factors such as c-Jun, JunD, ATF-2, and Elk-1, which become activated after exposure to cellular stresses (9Livingstone C. Patel G. Jones N. EMBO J. 1995; 14: 1785-1797Crossref PubMed Scopus (478) Google Scholar, 10Gupta S. Campbell D. Dérijard B. Davis R.J. Science. 1995; 267: 389-393Crossref PubMed Scopus (1347) Google Scholar, 11Cavigelli M. Dolfi F. Claret F.-X. Karin M. EMBO J. 1995; 14: 5957-5964Crossref PubMed Scopus (491) Google Scholar, 12Whitmarsh A.J. Shore P. Sharrocks A.D. Davis R.J. Science. 1995; 269: 403-406Crossref PubMed Scopus (884) Google Scholar). Mammalian p38 was originally identified in murine pre-B cells transfected with the lipopolysaccharide complex receptor CD14 and in macrophages where it is activated in response to lipopolysaccharide (13Han J. Lee J.-D. Bibbs L. Ulevitch R.J. Science. 1994; 265: 808-811Crossref PubMed Scopus (2438) Google Scholar). The amino acid sequence of p38 is most similar to HOG-1, a MAP kinase homologue that lies in a signaling pathway that restores the osmotic gradient across the plasma membrane of Saccharomyces cerevisiae in response to increased external osmolarity (14Brewster J.L. de Valoir T. Dwyer N.D. Winter E. Gustin M.C. Science. 1993; 259: 1760-1763Crossref PubMed Scopus (1056) Google Scholar). Like ERKs and JNKs, p38 requires phosphorylation of a closely spaced tyrosine and threonine for activation. However, the enzyme is distinguished by the sequence TGY in the activation domain, which differs from the TEY sequence found in ERKs, and the TPY sequence in the JNK and MAP kinase homologues. In addition to hyperosmotic shock, p38 is activated by a wide spectrum of stimuli such as physicochemical stresses, lipopolysaccharide, and cytokines (13Han J. Lee J.-D. Bibbs L. Ulevitch R.J. Science. 1994; 265: 808-811Crossref PubMed Scopus (2438) Google Scholar, 15Lee J.C. Laydon J.T. McDonnel P.C. Gallagher T.F. Kumar S. Green D. McNulty D. Blumenthal M.J. Heys J.R. Landvatter S.W. Nature. 1994; 372: 739-746Crossref PubMed Scopus (3175) Google Scholar, 16Lee J.C. Young P.R. J. Leukocyte Biol. 1996; 59: 152-157Crossref PubMed Scopus (376) Google Scholar, 17Raingeaud J. Gupta S. Rogers J.S. Dickens M. Han J. Ulevitch R.J. Davis R.J. J. Biol. Chem. 1995; 270: 7420-7426Abstract Full Text Full Text PDF PubMed Scopus (2061) Google Scholar). Despite rapid progress in the elucidation of structural elements of the p38 pathway, the physiological consequences of its stimulation by stress agents largely remain to be defined. One of the downstream targets of p38 is the MAPKAP kinase-2, which can activate the transcription factors CREB and ATF-1 (18Tan Y. Rose J. Zhang A. Cariati S. Cohen P. Comb M.J. EMBO J. 1996; 15: 4629-4642Crossref PubMed Scopus (571) Google Scholar) and phosphorylate heat-shock protein hsp27 (19Rouse J. Cohen P. Trigon S. Morange M. Alonso-Llamarazes A. Zamanillo D. Hunt T. Nebrada A.R. Cell. 1994; 78: 1027-1037Abstract Full Text PDF PubMed Scopus (1523) Google Scholar, 20Cuenda A. Rouse J. Doza Y.N. Meier R. Cohen P. Gallagher T.F. Young P.R. Lee J.C. FEBS Lett. 1995; 364: 229-233Crossref PubMed Scopus (1991) Google Scholar). It is assumed that hsp27 phosphorylation promotes the polymerization of actin and so counteracts the disruptive effects of stress on actin microfilaments (21Lavoie J.N. Hickey E. Weber L.A. Landry J. J. Biol. Chem. 1993; 268: 24210-24214Abstract Full Text PDF PubMed Google Scholar). A number of evidences further that p38 a in and of p38 such as potently the of and P. P. D. A. Laydon J. Lee J. 1993; PubMed Scopus Google Scholar). of and was to be to inhibition of which is through the in the of A. J. D. J. 1995; Google Scholar). In addition, inhibition of p38 found to and factor that p38 may R. A. S. Lee J.C. G. Cohen P. EMBO J. 1996; 15: PubMed Scopus Google Scholar). In p38 in the activation of multiple transcription such as J. Gupta S. Rogers J.S. Dickens M. Han J. Ulevitch R.J. Davis R.J. J. Biol. Chem. 1995; 270: 7420-7426Abstract Full Text Full Text PDF PubMed Scopus (2061) Google Scholar, J. A.J. T. Dérijard B. Davis R.J. Cell. Biol. 1996; PubMed Scopus Google J. A.J. T. Dérijard B. Davis R.J. Cell. Biol. 1996; PubMed Scopus Google and c-Jun E. A. M.J. Cohen P. Curr. Biol. 1996; 6: Full Text Full Text PDF PubMed Scopus Google D. Science. 1996; PubMed Scopus Google L. J.M. R. S. A. 1995; PubMed Scopus Google and NF-κB R. A. S. Lee J.C. G. Cohen P. EMBO J. 1996; 15: PubMed Scopus Google Scholar). The activator NF-κB is a the of cytokines and many gene (reviewed in Refs. T. Immunol. 1994; PubMed Scopus Google and M. 1995; PubMed Scopus Google Scholar). The factor is by a of or stimuli including cell and lipopolysaccharide, as as and In NF-κB in the as an complex to a called stimulation of NF-κB is activated by the of nuclear in the NF-κB to nuclear and binding of NF-κB to elements It found that the of is by its an which to the of S. EMBO J. 1995; 14: PubMed Scopus Google Scholar). A number of evidences further that reactive oxygen are the in the of NF-κB activation M. 1995; PubMed Scopus Google Scholar). is by the that NF-κB is activated in many cell to hydrogen R. P. EMBO J. PubMed Scopus Google Scholar, M. J. Immunol. 1995; PubMed Scopus Google and activation in response to stimuli so is by a of R. P. EMBO J. PubMed Scopus Google Scholar, R. G. EMBO J. 1993; PubMed Scopus Google Scholar). it is assumed that the of which is stimulated by stress a kinase that in turn many of the stimuli to NF-κB and p38 activation are we to the relationship between p38 and A of p38 in NF-κB activation by the that potently NF-κB activity R. A. S. Lee J.C. G. Cohen P. EMBO J. 1996; 15: PubMed Scopus Google Scholar). that stress such as activate p38 and NF-κB, stimuli including and hyperosmotic trigger p38. In addition, the that prevented NF-κB activation not but increased p38 activity. However, of p38 activation by a p38 inhibitor or a dominant-negative MAP kinase mutant NF-κB-dependent gene expression without interfering with NF-κB DNA binding activity. These indicate that activation of NF-κB and p38 on separate pathways but may converge downstream at the of The cell and cells were in with of and of were from was a of A from was by F. and and the p38 inhibitor by J. Lee of p38 kinase activity was expression of a p38 that was by the and by L. E. which as a p38 was in by S. Campbell D. Dérijard B. Davis R.J. Science. 1995; 267: 389-393Crossref PubMed Scopus (1347) Google Scholar). To the specificity of p38 the were in E. and by N. Cell. Biol. 1996; PubMed Google and 1994; Google Scholar). To the activity of NF-κB, cells were transfected with a gene by S. J. Biol. 1996; PubMed Scopus Google Scholar). The EMBO J. PubMed Scopus Google Scholar) as a A expression (9Livingstone C. Patel G. Jones N. EMBO J. 1995; 14: 1785-1797Crossref PubMed Scopus (478) Google Scholar). A dominant-negative expression of J. A.J. T. Dérijard B. Davis R.J. Cell. Biol. 1996; PubMed Scopus Google Scholar) was originally from R. J. of cells were by the S. J. Biol. 1996; PubMed Scopus Google Scholar). cells for kinase and for were on and and transfected after cells were either or stimulated with the or cells were and for p38 kinase or were in DTT, and at at for of the were in of DTT, a of of was in are in p38 activity was by a kinase as with the cells were in of DTT, and to cellular of and were p38 was by the addition of of a of at for the were with in and in The were by two in kinase DTT, The kinase was by of kinase of and of as for at the was by the addition of were on a by and by of NF-κB and AP-1 DNA binding cells were as J. 1995; PubMed Scopus Google Scholar). were in a of of binding DTT, of as of and of the a binding at were on a and in The of the used to the DNA binding activity of NF-κB and AP-1 were as are NF-κB, AP-1, The were with and kinase and The were from on p38 MAP kinase is known to be activated by a of cellular To kinase activity we p38 in cells and p38 activity in a with as The stress such as the and hyperosmotic of stimulated p38 activity to as as and of the A and p38 activity was also strongly by the and to a by The with and in of cells with hydrogen only a in p38 and in stimulation by hydrogen was only activity. In we the activation of transcription factor NF-κB, which is activated by stimuli many of p38 In to p38, NF-κB was not activated by and activation of NF-κB was after with not activate NF-κB in in cell activation by was R. P. EMBO J. PubMed Scopus Google Scholar, M. J. Immunol. 1995; PubMed Scopus Google NF-κB was also activated in response to hydrogen further the effects of a and an inhibitor of which to activate NF-κB EMBO J. 1995; 14: PubMed Scopus Google Scholar). acid strongly p38 and NF-κB activation activated NF-κB but effects on p38 activity. that activation of p38 and NF-κB are only stress activate either p38 MAP kinase or NF-κB, thus the existence of pathways. of p38 activation to activity R. A. S. Lee J.C. G. Cohen P. EMBO J. 1996; 15: PubMed Scopus Google Scholar). investigated the of p38 MAP kinase to phosphorylate NF-κB in In the the were in E. as or and with p38 in that of the NF-κB including the of and were by p38. In contrast, was strongly by p38 MAP kinase. The results indicate that NF-κB is to as a of p38. NF-κB important transcription factor is The factor a or complex of of the and ERKs, JNKs, and p38 are in activation of c-Jun and (9Livingstone C. Patel G. Jones N. EMBO J. 1995; 14: 1785-1797Crossref PubMed Scopus (478) Google Scholar, H. D. A. P. P. EMBO J. 1995; 14: PubMed Scopus Google Scholar). activation of AP-1 DNA binding an with the AP-1 from the preferentially to and but not to H. D. A. P. P. EMBO J. 1995; 14: PubMed Scopus Google Scholar). In cellular used for the of NF-κB, it was found that AP-1 DNA binding activity was increased in response to stress stimuli and TNF, either or in potently AP-1 activation. A activation was also in response to with and hydrogen not further the or of de protein in response to stress on it can be that activation of AP-1 by PMA, TNF, and cellular different of MAP kinases distinct AP-1 physicochemical stresses preferentially lead to and activate c-Jun H. D. A. P. P. EMBO J. 1995; 14: PubMed Scopus Google Scholar, M. J. Biol. Chem. 1995; 270: Full Text Full Text PDF PubMed Scopus Google Scholar). The in to NF-κB, a of extracellular stimuli converge at the of The activation of NF-κB and AP-1 is by signaling pathways M. 1995; PubMed Scopus Google Scholar). NF-κB is a factor activation is by a of In contrast, to the activation of AP-1 by inducing and transcription M. R. EMBO J. 1993; PubMed Scopus Google Scholar, H. M. S. A. 1994; PubMed Scopus Google Scholar). To the of in p38 activation we used the pyrrolidine an and A that of cells with increased p38 kinase activity in response to stimuli with and AP-1 activation was also by In contrast, NF-κB activation in response to TNF, in was abolished The that p38 and NF-κB are by to AP-1, p38 activity is by To a on p38 kinase we p38 from cells with in kinase activity was of p38 with different of or not in that p38 activity only in further to the signaling pathways by the of The small GTPases Rac and Cdc42 identified as important to the JNK and p38 activation cascades (4Minden A. Lin A. Claret F.-X. Abo A. Karin M. Cell. 1995; 81: 1147-1157Abstract Full Text PDF PubMed Scopus (1450) Google Scholar, 5Coso O.A. Chiariello M. Yu J.-C. Teramoto H. Crespo P. Xu N. Miki T. Gutkind J.S. Cell. 1995; 81: 1137-1146Abstract Full Text PDF PubMed Scopus (1574) Google Scholar). The activity of Rac and Cdc42 but not of is by A from C. M. J. G. C. M. J. Biol. Chem. 1995; 270: Full Text Full Text PDF PubMed Scopus Google Scholar). of cells with A a inhibition of p38 activation the of Rac and Cdc42 in p38 kinase activation In with the AP-1 activation was also by A in response to was for NF-κB that signals to NF-κB activation are not through In the it not be that in the p38 kinase pathway with p38 and in and cells and investigated the effects on expression of a with different of the p38 not NF-κB activity in or stimulated cells of of ATF-2, either or in with p38, was ineffective in expression of the In contrast, of a NF-κB which as a strongly increased of on cells and cells were transfected with different of an expression with the NF-κB-dependent In the and of were and the were to with the (9Livingstone C. Patel G. Jones N. EMBO J. 1995; 14: 1785-1797Crossref PubMed Scopus (478) Google Scholar). In expression of NF-κB and p38 were in the were stimulated with and and for of NF-κB gene activity as in The were with similar The activity of p38 is by the In cells we found that also strongly prevented expression of a gene in response to a of and The for inhibition of NF-κB activity to the effects on p38 kinase activity in electrophoretic mobility shift however, was to activation of NF-κB DNA binding activity further the effects of the dual specificity kinase which identified as a activator of p38 J. A.J. T. Dérijard B. Davis R.J. Cell. Biol. 1996; PubMed Scopus Google Scholar, J. Lee J.-D. Y. Z. L. Ulevitch R. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). of a kinase mutant abolished p38 activation by and In a inhibition of NF-κB activity was also results indicate a complex of of p38 and NF-κB. by the activation of of NF-κB by the of in the p38 activation. may further downstream in the cell either by effects of p38 on or NF-κB a transcription factor that is activated by a of that also activation of MAP In the of its inhibitor is and the DNA binding NF-κB to the cell nucleus. the protein kinase is kinases including protein kinase and and a kinase to either or in (reviewed in Refs. T. Immunol. 1994; PubMed Scopus Google and L. T. Cell. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). of the MAP kinase modules further in NF-κB activation. of JNK by upstream kinase in NF-κB and kinase NF-κB activity in cellular M. S. T. S. M. J. S. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). However, was it that at least in cell JNK and NF-κB activation are two separate Z. H. Karin M. Cell. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, G. A. A. Woodgett J.R. C. M. Science. PubMed Scopus Google Scholar). In addition, p38 may be to NF-κB activation a pharmacological inhibitor of p38 NF-κB-dependent R. A. S. Lee J.C. G. Cohen P. EMBO J. 1996; 15: PubMed Scopus Google and In we that the signaling pathways to p38 and NF-κB activation can be many stimuli activating either of are not several agents such as and activate p38 and NF-κB Z. Dérijard B. Wu I.H. Davis R.J. Science. 1994; 265: 806-808Crossref PubMed Scopus (539) Google Scholar, J. Lee J.-D. Bibbs L. Ulevitch R.J. Science. 1994; 265: 808-811Crossref PubMed Scopus (2438) Google Scholar, 17Raingeaud J. Gupta S. Rogers J.S. Dickens M. Han J. Ulevitch R.J. Davis R.J. J. Biol. Chem. 1995; 270: 7420-7426Abstract Full Text Full Text PDF PubMed Scopus (2061) Google J. Cohen P. Trigon S. Morange M. Alonso-Llamarazes A. Zamanillo D. Hunt T. Nebrada A.R. Cell. 1994; 78: 1027-1037Abstract Full Text PDF PubMed Scopus (1523) Google Scholar, M. 1995; PubMed Scopus Google in of p38 including and hyperosmotic not activate NF-κB. stimuli of MAP kinases such as agents or were not found to trigger NF-κB activation. that cellular stress or of a stress response where different forms of cellular stress A distinct to cellular stresses is by the that PMA, which is a NF-κB activator in several cell p38 but not NF-κB activation in In to NF-κB many stress stimuli were found to lead to the activation of of multiple stress stimuli at the of AP-1 is different forms of stimuli preferentially distinct MAP kinase cascades (9Livingstone C. Patel G. Jones N. EMBO J. 1995; 14: 1785-1797Crossref PubMed Scopus (478) Google Scholar, H. D. A. P. P. EMBO J. 1995; 14: PubMed Scopus Google Scholar, M. J. Biol. Chem. 1995; 270: Full Text Full Text PDF PubMed Scopus Google Scholar). These in turn AP-1 activation at different including at the and and AP-1 The of p38 in induction of AP-1 by the that inhibition of p38 kinase prevented the of and c-Jun in response to stress stimuli E. A. M.J. Cohen P. Curr. Biol. 1996; 6: Full Text Full Text PDF PubMed Scopus Google Scholar). as a in of a of different forms of activation of NF-κB by stimuli so is by that are the for NF-κB activation T. Immunol. 1994; PubMed Scopus Google Scholar, M. 1995; PubMed Scopus Google Scholar). of and as as in response to growth and cytokines also to be by Y. M. Xu J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, T.F. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). we were to that p38 activity was not but by in p38 activity was by an activation of AP-1 that several AP-1 activation M. R. EMBO J. 1993; PubMed Scopus Google Scholar, H. M. S. A. 1994; PubMed Scopus Google Scholar). to AP-1 M. R. EMBO J. 1993; PubMed Scopus Google p38 was also modestly activated by hydrogen is in with in to and ERKs, the p38 pathway is only activated by several such as hydrogen peroxide, or M. 1996; Google Scholar, Davis R.J. J.M. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). many of that of p38, are of distinct of Davis R.J. S. A. 1996; PubMed Scopus Google Scholar, D. Davis R.J. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). A physiological of may be it that in of cells are activated where p38 is only activated in Avruch J. Woodgett J.R. J.M. T. J. Biol. Chem. 1994; 269: Full Text PDF PubMed Google Scholar, Rubie E. E. L.A. L. J. Woodgett J.R. Curr. Biol. 1996; 6: Full Text Full Text PDF PubMed Scopus Google Scholar). a shift in the cellular may cells to trigger p38 or the JNK and ERK pathways. of the pathways to activation of p38 and NF-κB was found by the of small of the such as Rac and Cdc42 that p38 and JNK activation (4Minden A. Lin A. Claret F.-X. Abo A. Karin M. Cell. 1995; 81: 1147-1157Abstract Full Text PDF PubMed Scopus (1450) Google Scholar, 5Coso O.A. Chiariello M. Yu J.-C. Teramoto H. Crespo P. Xu N. Miki T. Gutkind J.S. Cell. 1995; 81: 1137-1146Abstract Full Text PDF PubMed Scopus (1574) Google Scholar) are by A M. J. G. C. M. J. Biol. Chem. 1995; 270: Full Text Full Text PDF PubMed Scopus Google Scholar). Whereas A not with NF-κB DNA binding p38 activation was strongly we that p38 and NF-κB activation are not pathways, results also that may further a dominant-negative mutant of as as a pharmacological inhibitor strongly NF-κB activity. However, activation of NF-κB DNA binding activity was not that p38 interfered with the of NF-κB. kinase we that in to the NF-κB DNA binding or the of are by p38. The to phosphorylate the that p38 the of NF-κB, which to become activated by phosphorylation at of the two G. H. M. J. Biol. Chem. 1995; 270: Full Text Full Text PDF PubMed Scopus Google Scholar, M.A. J. Biol. Chem. 1995; 270: Full Text Full Text PDF PubMed Scopus Google Scholar). However, it is that a kinase downstream in the p38 pathway, such as a of the NF-κB NF-κB to and with a number of transcription factors including AP-1, of the and (reviewed in Refs. G. H. M. J. Biol. Chem. 1995; 270: Full Text Full Text PDF PubMed Scopus Google and D. S. 1995; PubMed Scopus Google Scholar). To transcription factors that may become activated by p38 with the of NF-κB, we the of p38 and in NF-κB gene In we not an of NF-κB-dependent gene we that p38 may an A for a of pathways may be a of p38 on and Inhibition of p38 activation by dominant-negative or the related to gene expression by several and by several transcription and J. A.J. T. Dérijard B. Davis R.J. Cell. Biol. 1996; PubMed Scopus Google Scholar). However, p38 not gene expression as such as the are not J. A.J. T. Dérijard B. Davis R.J. Cell. Biol. 1996; PubMed Scopus Google Scholar). of of the p38 pathway on gene expression. In indicate that the pathways in p38 and NF-κB activation are important stress response is through in the activation of NF-κB in the of cellular stresses an pathway that is mediated by of pathways may further downstream in the cell nucleus at the of R. R. J. N. C. R. J. and L. E. for F. and for and J. Lee for also R. for