Stress-induced stimulation of early growth response gene-1 by p38/stress-activated protein kinase 2 is mediated by a cAMP-responsive promoter element in a MAPKAP kinase 2-independent manner.
The p38/stress-activated protein kinase2 (p38/SAPK2) is activated by cellular stress and proinflammatory cytokines. Several transcription factors have been reported to be regulated by p38/SAPK2, and this kinase is involved in the control of expression of various genes. In human Jurkat T-cells, induction of the early growth response gene-1 (egr-1) by anisomycin is completely inhibited by SB203580, a specific inhibitor of p38/SAPK2a and -b. Northern blot and reporter gene experiments indicate that this block is at the level of mRNA biosynthesis. Using mutants of the egr-1 promoter, we demonstrate that a distal cAMP-responsive element (CRE; nucleotides -134 to -126) is necessary to control egr-1 induction by p38/SAPK2. Pull-down assays indicate that phospho-CRE binding protein (CREB) and phospho-activating transcription factor-1 (ATF1) bind to this element in a p38/SAPK2-dependent manner. In response to anisomycin, two known CREB kinases downstream to p38/SAPK2, MAPKAP kinase 2 (MK2) and mitogen- and stress-activated kinase 1 (MSK1), show increased activity. However, in MK2 -/- fibroblasts derived from mice carrying a disruption of the MK2 gene, the phosphorylation of CREB and ATF1 and the expression of egr-1 reach levels comparable with wild type cells. This finding excludes MK2 as an involved enzyme. We conclude that egr-1 induction by anisomycin is mediated by p38/SAPK2 and probably by MSK1. Phosphorylated CREB and ATF1 then bind to the CRE of the egr-1 promoter and cause a stress-dependent transcriptional activation of this gene.
Martin-Luther-University Halle-Wittenberg, Innovationskolleg Zellspezialisierung, Hoher Weg 8, D-06120 Halle, Germany.
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Rolli
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Kotlyarov
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Sakamoto
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Gaestel
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Neininger
D051697:Activating Transcription Factor 1; D000841:Anisomycin / Q000494:pharmacology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics*; D000242:Cyclic AMP / Q000235:genetics; D051786:Cyclic AMP Response Element Modulator; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D051766:Early Growth Response Protein 1; D004789:Enzyme Activation; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D017874:Immediate-Early Proteins; D047908:Intracellular Signaling Peptides and Proteins; D019169:Jurkat Cells; D020928:Mitogen-Activated Protein Kinases; D009154:Mutation; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D012045:Regulatory Sequences, Nucleic Acid; D012097:Repressor Proteins; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D014157:Transcription Factors / Q000235:genetics*; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2
D051697:Activating Transcription Factor 1; D000841:Anisomycin; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D000242:Cyclic AMP; D051786:Cyclic AMP Response Element Modulator; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; D007093:Imidazoles; D017874:Immediate-Early Proteins; D047908:Intracellular Signaling Peptides and Proteins; D020928:Mitogen-Activated Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011725:Pyridines; D012097:Repressor Proteins; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D014157:Transcription Factors; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2; C497325:EGR1 protein, human; C116919:mitogen and stress-activated protein kinase 1; C093642:SB 203580