MSKs are required for the transcription of the nuclear orphan receptors Nur77, Nurr1 and Nor1 downstream of MAPK signalling

Darragh, Joanne; Soloaga, Ana; Beardmore, Victoria A.; Wingate, Andrew D.; Wiggin, Giselle R.; Peggie, Mark; Arthur, J. Simon C.

doi:10.1042/bj20050196

Cited by 106 publications

(115 citation statements)

References 72 publications

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“…In addition to a MEF2 site, the nur77 promoter is also regulated by SRE and AP-1/CRE-like sequences. In most cell types the MAPK-dependent transcription of nur77 requires the phosphorylation of CREB by MSKs [35]. However, in T cells TCR-induced nur77 transcription, while dependent on MAPK signalling, is independent of MSKs and CREB phosphorylation [49].…”

Section: Discussionmentioning

confidence: 99%

“…Total RNA was reverse-transcribed using iScript (BioRad), and real-time PCR carried out using Sybrgreen based detection methods (BioRad). Primers for 18s, nur77, nor1 and egr3 have been described previously [35,49]. Primer sequences for ERK5, IL-2, IL-4, IL-13, IFN-g and IkBa are listed in Table 3.…”

Section: Quantitative Pcrmentioning

confidence: 99%

“…Transcription of both nur77 and nor1 is upregulated by TCR signalling in T cells [34], although the transcription of nor1 is likely to be independent of MEF2D [35]. Based on overexpression transgenics, nur77 has been suggested to regulate T-cell apoptosis [36].…”

Section: Introductionmentioning

confidence: 99%

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ERK5 regulation in naïve T‐cell activation and survival

et al. 2008

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ERK5 has been implicated in regulating the MEF2-dependent genes Klf2 and nur77 downstream of the TCR and the maintenance of expression of CD62L on peripheral T cells. Based on this data, knockout of ERK5 would be predicted to compromise T-cell development and the maintenance of T cells in the periphery. Using an ERK5 conditional knockout, driven by CD4-CRE or Vav-CRE transgenes resulting in the loss of ERK5 in T cells, we have found that ERK5 is not required for T-cell development. In addition, normal numbers of T cells were found in the spleens and lymph nodes of these mice. We also find that TCR stimulation is not a strong signal for ERK5 activation in primary murine T cells. ERK5 was found to contribute to the induction of Klf2 but not nur77 mRNA following TCR activation. Despite the reduction in Klf2 mRNA, no effect was seen in ERK5 knockouts on either the mRNA levels for the Klf2 target genes CD62L, CCR7 and S1P, or the cell surface expression of CD62L. These results suggest that while ERK5 does contribute to Klf2 regulation in T cells, it is not essential for the expression of CD62L or T-cell survival. IntroductionMitogen-activated protein kinase (MAPK) cascades are important mediators of cellular responses to a variety of signals, including growth factors, cytokines and cellular stresses. Fourteen MAPK isoforms have been identified in mammalian cells, which can broadly be divided into four groups, the classical MAPK (ERK1 and ERK2), p38 MAPK, JNK and atypical MAPK, which include ERK5, ERK3 and ERK8 [1][2][3][4][5].ERK5 is an unusual MAPK, as it contains a large C-terminal domain in addition to the MAPK domain [2,6,7]. The precise role of the C-terminal domain is unclear; however, it has been shown to be involved in the regulation of ERK5 sub-cellular localisation [8]. The C-terminal domain has also been suggested to act as a transcriptional co-activator for the MEF2 transcription factors [9]. In cells, ERK5 is activated in response to specific growth factors including EGF, as well as by some stresses, such as sorbitol and hydrogen peroxide [10,11]. Like other MAPK, ERK5 is activated by phosphorylation on its TXY motif downstream of a MAPK kinase. MEK5 was originally proposed as the kinase responsible for ERK5 activation, based on its interaction with ERK5 in a yeast two-hybrid assay [12]. This finding was later confirmed by the observation that embryonic fibroblasts isolated from MEK5 knockout mice were unable to activate ERK5 [13]. MEK5 is activated downstream of a MAPK kinase kinase Ã These authors contributed equally to this study. 2534(MAP3 K), most probably MEKK2. ERK5 signalling has been reported to be deficient in EGF and FGF stimulated embryonic fibroblast cells from MEKK2 knockout mice suggesting that MEKK2 is the predominant MAP3 K for MEK5, downstream of these signals [14,15]. It is not clear, however, if MEKK2 is the only MAP3 K able to activate the ERK5 pathway. Mouse knockouts of either ERK5 or MEK5 are embryonic lethal, however knockouts of MEKK2 are viable and do not exhibit obvious phen...

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Section: Discussionmentioning

confidence: 99%

Section: Quantitative Pcrmentioning

confidence: 99%

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ERK5 regulation in naïve T‐cell activation and survival

et al. 2008

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“…Nr4a1 (also known as nur77 and NGFI-B) belongs to a subfamily of orphan nuclear receptors, whose other members are Nr4a2 [also known as Rnr-1 (ribonucleotide reductase-1), Not, and Nurr1] and Nr4a3 [also known as Nor-1 (neuron-derived orphan receptor-1) and Tec], all of which function as transcription factors (Ryseck et al, 1989;Steinmetz et al, 2001). Several studies have implicated Nr4a1 and Nr4a2 as CREB target genes (Fass et al, 2003;Darragh et al, 2005;von Hertzen and Giese, 2005ab). Also, Fass et al (2003) observed that forskolin-induced Nr4a1 expression was increased by TSA treatment, whereas Nr4a3 expression was not enhanced by TSA (Fass et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Histone Deacetylase Inhibitors Enhance Memory and Synaptic Plasticity via CREB: CBP-Dependent Transcriptional Activation

Vecsey¹,

Hawk²,

Lattal³

et al. 2007

Journal of Neuroscience

759

761

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Histone deacetylase (HDAC) inhibitors increase histone acetylation and enhance both memory and synaptic plasticity. The current model for the action of HDAC inhibitors assumes that they alter gene expression globally and thus affect memory processes in a nonspecific manner. Here, we show that the enhancement of hippocampus-dependent memory and hippocampal synaptic plasticity by HDAC inhibitors is mediated by the transcription factor cAMP response element-binding protein (CREB) and the recruitment of the transcriptional coactivator and histone acetyltransferase CREB-binding protein (CBP) via the CREB-binding domain of CBP. Furthermore, we show that the HDAC inhibitor trichostatin A does not globally alter gene expression but instead increases the expression of specific genes during memory consolidation. Our results suggest that HDAC inhibitors enhance memory processes by the activation of key genes regulated by the CREB:CBP transcriptional complex.

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“…MSKs are able to regulate transcription by the phosphorylation of both transcription factors, including CREB (cAMP-response-element-binding protein) and ATF1 (activating transcription factor) [1][2][3][4][5][6], and the chromatinassociated proteins HMG-14 (high-mobility group 14) and histone H3 [7][8][9][10]. Genes reported to be regulated by MSK downstream of CREB or ATF1 include c-fos [11], junB [4], MUC5A (mucin 5A) [12] and genes encoding the NR4A group of nuclear orphan receptors [13].…”

Section: Introductionmentioning

confidence: 99%

Identification of novel phosphorylation sites in MSK1 by precursor ion scanning MS

McCoy

Macdonald

Morrice

et al. 2007

Biochemical Journal

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MSK1 (mitogen-and stress-activated kinase 1) is a dual kinase domain protein that acts downstream of the ERK1/2 (extracellular-signal-regulated kinase 1/2) and p38 MAPK (mitogenactivated protein kinase) signalling pathways in cells. MSK1, and its related isoform MSK2, phosphorylate the transcription factors CREB (cAMP-response-element-binding protein) and ATF1 (activating transcription factor 1), and the chromatin proteins histone H3 and HMGN1 (high-mobility-group nucleosomalbinding protein 1) in response to either mitogenic stimulation or cellular stress. MSK1 activity is tightly regulated in cells, and activation requires the phosphorylation of MSK1 by either ERK1/2 or p38α. This results in activation of the C-terminal kinase domain, which then phosphorylates further sites in MSK1, leading to the activation of the N-terminal kinase domain and phosphorylation of substrates. Here, we use precursor ion scanning MS to identify five previously unknown sites in MSK1: Thr 630 , Ser 647 , Ser 657 , Ser 695 and Thr 700 . One of these sites, Thr 700 , was found to be a third site in MSK1 phosphorylated by the upstream kinases ERK1/2 and p38α. Mutation of Thr 700 resulted in an increased basal activity of MSK1, but this could be further increased by stimulation with PMA or UV-C radiation. Surprisingly, however, mutation of Thr 700 resulted in a dramatic loss of Thr 581 phosphorylation, a site essential for activity. Mutation of Thr 700 and Thr 581 to an alanine residue resulted in an inactive kinase, while mutation of both sites to an aspartic acid residue resulted in a kinase with a significant basal activity that could not be further stimulated. Together these results are consistent with a mechanism by which Thr 700 phosphorylation relieves the inhibition of MSK1 by a C-terminal autoinhibitory helix and helps induce a conformational shift that protects Thr 581 from dephosphorylation.

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MSKs are required for the transcription of the nuclear orphan receptors Nur77, Nurr1 and Nor1 downstream of MAPK signalling

Cited by 106 publications

References 72 publications

ERK5 regulation in naïve T‐cell activation and survival

ERK5 regulation in naïve T‐cell activation and survival

Histone Deacetylase Inhibitors Enhance Memory and Synaptic Plasticity via CREB: CBP-Dependent Transcriptional Activation

Identification of novel phosphorylation sites in MSK1 by precursor ion scanning MS

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