Synergistic activation of the <i>mkp‐1</i> gene by protein kinase A signaling and USF, but not c‐Myc

Sommer, Anette; Burkhardt, Hannelore; Keyse, Stephen M.; Lüscher, Bernhard

doi:10.1016/s0014-5793(00)01566-0

Cited by 46 publications

(49 citation statements)

References 39 publications

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“…-1913 Innate immunity Here we demonstrate that transcriptional regulation of MKP-1 expression requires a CREB/AP-1 sequence located in the promoter. Although another CRE box has been described in the MKP-1 promoter [36], it is outside of the sequence susceptible to regulation by M-CSF or LPS. Members of the AP1 or CREB-ATF family of nuclear factors can form homodimeric or heterodimeric protein complexes, which transduce distinct signals and exert discrete transcriptional responses on various promoter targets [53].…”

Section: Discussionmentioning

confidence: 99%

“…However, the CRE/AP-1 box (TGACGTCT), which has been reported to be involved in the regulation of several genes [43], was critical. This box is also present in the promoter of the human gene [36]. When we mutated either the CRE or the AP-1 box, M-CSF-or LPSdependent inducibility was lost (Fig.…”

Section: Mkp-1 Expression Induced By M-csf or Lps Is Regulated By A Cmentioning

confidence: 96%

“…box is also present in the promoter of the human gene [36]. When we mutated either the CRE or the AP-1 box, M-CSF-or LPSdependent inducibility was lost (Fig.…”

Section: Mkp-1 Expression Induced By M-csf or Lps Is Regulated By A Cmentioning

confidence: 98%

“…Like many other immediate-early genes, MKP-1 expression is regulated mainly at the transcriptional level. The chromatin on the MKP-1 locus is altered following treatment with arsenite [33] and several transcription factors (including Sp1, Sp3, AP-1 and USF) influence the MKP-1 gene transcription in response to growth factors and stress stimuli [34][35][36]. MKP-1 is silenced transcriptionally by the FBI1-14-3-3b complex [37].…”

Section: Introductionmentioning

confidence: 99%

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CREB and AP‐1 activation regulates MKP‐1 induction by LPS or M‐CSF and their kinetics correlate with macrophage activation versus proliferation

et al. 2009

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MAPK phosphatase-1 (MKP-1) is a protein phosphatase that plays a crucial role in innate immunity. This phosphatase inactivates ERK1/2, which are involved in two opposite functional activities of the macrophage, namely proliferation and activation. Here we found that although macrophage proliferation and activation induce MKP-1 with different kinetics, gene expression is mediated by the proximal promoter sequences localized between À380 and À180 bp. Mutagenesis experiments of the proximal element determined that CRE/AP-1 is required for LPS-or M-CSF-induced activation of the MKP-1 gene. Moreover, the results from gel shift analysis and chromatin immunoprecipitation indicated that c-Jun and CREB bind to the CRE/AP-1 box. The distinct kinetics shown by M-CSF and LPS correlates with the induction of JNK and c-jun, as well as the requirement for Raf-1. The signal transduction pathways that activate the induction of MKP-1 correlate kinetically with induction by M-CSF and LPS.Key words: Activation . Kinases . Macrophage . Phosphatases . Proliferation IntroductionMacrophages perform critical functions during the immune response. These cells are regulators of homeostasis and play an important role in innate and acquired immunity during infection, tumor growth, and wound healing [1]. In response to needs, tissue macrophages proliferate, further differentiate to more specialized macrophagic populations, or become activated. Macrophages, like many other cells of the immune system, are produced in large excess and most undergo apoptosis [2].In the presence of M-CSF, macrophages differentiate and proliferate. However, the proliferation of these cells is blocked when they are activated by Gram-negative LPS or by . Activation causes many biochemical, morphological and functional modifications. Macrophage response to M-CSF and LPS involves the phosphorylation of the three members of the MAPK family [4].MAPK are critical components of signal transduction pathways activated by a range of stimuli and they mediate a number of physiological and pathological changes in cell function [5,6]. MAPK activation requires phosphorylation on a threonine and tyrosine residue located in the activation loop. This process is reversible even in the continued presence of activating stimuli, thereby indicating that protein phosphatases regulate MAPK [7]. Although MAPK are conserved evolutionary pathways present in eukaryotic cells, the kinetics of activation and their subcellular compartmentalization are cell type-specific, and they orchestrate differential cellular responses. For example, in neuronal cells, sustained MAPK phosphorylation of even days is required for cellular activation or differentiation, while in fibroblasts, phosphorylation of this kinase family is very short. In contrast, to Immunol. 2009. 39: 1902-1913 Cristina Casals-Casas et al. 1902 achieve proliferation, extended activation of MAPK is required in these cells [6,7]. The correct spatio-temporal regulation of MAPK signalling is crucial in determining cellular responses to g...

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Section: Discussionmentioning

confidence: 99%

Section: Mkp-1 Expression Induced By M-csf or Lps Is Regulated By A Cmentioning

confidence: 96%

“…box is also present in the promoter of the human gene [36]. When we mutated either the CRE or the AP-1 box, M-CSF-or LPSdependent inducibility was lost (Fig.…”

Section: Mkp-1 Expression Induced By M-csf or Lps Is Regulated By A Cmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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CREB and AP‐1 activation regulates MKP‐1 induction by LPS or M‐CSF and their kinetics correlate with macrophage activation versus proliferation

et al. 2009

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“…A comparison of the 5Ј-flanking sequence of the murine and the human genes revealed two conserved Ca 2ϩ /cAMP-responsive elements (CREs) and one E box motif in the promoter region of MKP-1. Recently, the upstream stimulatory factor, a member of the basic/helix-loop-helix/leucine zipper family has been shown to bind to the E box motif and transactivate MKP-1 expression in synergy with protein kinase A (10). Since multiple intracellular signals can target MKP-1 gene expression, it is likely that regulatory elements other than the CREs and the E box motifs may influence its transcription.…”

mentioning

confidence: 99%

MAP Kinase Phosphatase-1 Gene Transcription in Rat Neuroendocrine Cells Is Modulated by a Calcium-sensitive Block to Elongation in the First Exon

Ryser¹,

Tórtola²,

Haasteren³

et al. 2001

Journal of Biological Chemistry

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Transcriptional elongation of many eukaryotic, prokaryotic, and viral genes is tightly controlled, which contributes to gene regulation. Here we describe this phenomenon for the MAP kinase phosphatase 1 (MKP-1) immediate early gene. In rat GH4C1 pituitary cells, MKP-1 mRNA is rapidly and transiently induced by the thyrotropin-releasing hormone (TRH) and the epidermal growth factor EGF via transcriptional activation of the gene. Ca 2؉ signals are necessary for the induction of MKP-1 in response to TRH but not to EGF. Reporter gene analysis with the newly cloned rat promoter sequence shows only limited induction in response to various stimuli, including TRH or EGF. By nuclear run-on assays we demonstrate that in basal conditions, a strong block to elongation in the first exon regulates the MKP-1 gene and that stimulation with either TRH or EGF overcomes the block. Ca 2؉ signals are important to release the MKP-1 elongation block in a manner similar to the c-fos oncogene. These results suggest that a common mechanism of intragenic regulation may be conserved between MKP-1 and c-fos in mammalian cells.Long term cellular processes such as proliferation, differentiation, and neuronal plasticity are controlled by extracellular stimuli and require the synthesis of new gene products. Following stimulation, expression of immediate early genes (IEGs) precedes the expression of late response genes, the latter encoding for proteins implicated in specific functions. The best known IEG products are transcription factors such as c-Fos, c-Jun, and c-Myc, which control the expression of late response genes (1, 2). Not all IEGs encode for transcription factors. For instance, structural proteins like actin or tropomyosin, cytokines, and other regulatory proteins show a rapid and transient induction by growth factors (1).Recently, a group of dual specificity phosphatases have been identified as being IEG products induced by various stimuli (growth factors, stress, neurotransmittors, etc.; reviewed in Ref.3). These dual specificity (threonine/tyrosine) phosphatases have been named MAP kinase phosphatases (DSPs or MKPs), since they are effective in the inactivation of MAP kinases by dual dephosphorylation (4). MAP kinase phosphatase-1 (MKP-1/CL100/3CH134) is one example of this group of nuclear enzymes encoded by an IEG. Although MKP-1 gene transcription is activated by multiple signals, such as mitogens (5, 6), cytokines (7), oxidative stress (8), heat shock (8), or hypoxia (9), the precise mode of gene regulation of this immediate early gene by such stimuli remains unclear. A comparison of the 5Ј-flanking sequence of the murine and the human genes revealed two conserved Ca 2ϩ /cAMP-responsive elements (CREs) and one E box motif in the promoter region of MKP-1. Recently, the upstream stimulatory factor, a member of the basic/helix-loop-helix/leucine zipper family has been shown to bind to the E box motif and transactivate MKP-1 expression in synergy with protein kinase A (10). Since multiple intracellular signals can target MKP-1 gen...

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Control of dual‐specificity phosphatase‐1 expression in activated macrophages by IL‐10

et al. 2005

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Ligation of Toll-like receptors (TLR) on macrophages induces cytokines and mediators important for the control of pathogens. Macrophage activation has to be tightly controlled to prevent hyper-inflammation. Accordingly, the hallmarks of TLR-triggered signaling, nuclear translocation of NF-jB and phosphorylation of mitogen-activated protein kinases (MAPK), are transient events. We have mined microarray datasets for changes in the expression of phosphatases in resting and TLR-activated macrophages. Several members of the dual-specificity phosphatases (DUSP) were induced upon triggering TLR4 with LPS. Up-regulation of DUSP1 mRNA was transient after stimulation with LPS alone, but addition of the immunosuppressive cytokine IL-10 resulted in robust, continued DUSP1 expression. IL-10 also synergized with the antiinflammatory glucocorticoid dexamethasone in the induction of DUSP1 mRNA expression in activated macrophages, as well as in the inhibition of IL-6 and IL-12 production. Increased expression of DUSP1 in IL-10-treated activated macrophages was correlated with a faster down-regulation of p38 MAPK activation. Thus, these data suggest an operational link between IL-10 and inibition of p38 MAPK via sustained expression of DUSP1.

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Synergistic activation of the mkp‐1 gene by protein kinase A signaling and USF, but not c‐Myc

Cited by 46 publications

References 39 publications

CREB and AP‐1 activation regulates MKP‐1 induction by LPS or M‐CSF and their kinetics correlate with macrophage activation versus proliferation

CREB and AP‐1 activation regulates MKP‐1 induction by LPS or M‐CSF and their kinetics correlate with macrophage activation versus proliferation

MAP Kinase Phosphatase-1 Gene Transcription in Rat Neuroendocrine Cells Is Modulated by a Calcium-sensitive Block to Elongation in the First Exon

Control of dual‐specificity phosphatase‐1 expression in activated macrophages by IL‐10

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