MSK regulate TCR‐induced CREB phosphorylation but not immediate early gene transcription

Kaiser, Madlen; Wiggin, Giselle R.; Lightfoot, K; Arthur, J. Simon C.; Macdonald, Andrew

doi:10.1002/eji.200636606

Cited by 26 publications

(32 citation statements)

References 49 publications

(65 reference statements)

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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%

“…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].ERK5 has also been implicated in the regulation of Klf2 mRNA expression, as Klf2 mRNA levels were downregulated in ERK5 knockout embryos and siRNA against ERK5 reduced Klf2 mRNA expression in T cells [28]. This study also reported that siRNA against ERK5 surpressed cell surface CD62L expression, a known target gene of Klf2.…”

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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%

mentioning

confidence: 99%

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ERK5 regulation in naïve T‐cell activation and survival

et al. 2008

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“…Experiments based on in situ 3 H-thymidine and BrdU incorporation showed that 2-3% of epidermal LC are cycling (5) and that murine epidermal LC express the Ki67 proliferation-associated antigen (6). Several electron microscopic observations of LC undergoing mitosis within human epidermis have also been reported (7). Experimental data obtained in mice have suggested that under steady-state conditions the efflux of LC to local lymph nodes would be balanced by LC divisions within the epidermis, whereas under conditions severely depleting epidermal LC (such as UV-radiation), LC precursors would be recruited from the peripheral blood (8).…”

Section: Introductionmentioning

confidence: 98%

“…Following activation, MSK1 ⁄ 2 are able to phosphorylate transcription factors such as CREB and ATF1 (3,(7)(8)(9)(10). Through activation of these transcription factors, MSK1 ⁄ 2 regulate the expression of a number of specific immediate early genes such as c-fos, junB and egr1 (6,10,11).…”

Section: Introductionmentioning

confidence: 99%

The role of mitogen‐ and stress‐activated protein kinase 1 and 2 in chronic skin inflammation in mice

Bertelsen¹,

Iversen²,

Riis³

et al. 2010

Experimental Dermatology

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Mitogen-and stress-activated protein kinase 1 and 2 (MSK1 ⁄ 2) are two kinases phosphorylated by both ERK1 ⁄ 2 and p38 MAPK. Recently, MSK1 and 2 have been reported to act as negative regulators of acute inflammation. In this study, we investigated the role of MSK1 ⁄ 2 in chronic skin inflammation using an oxazolone-induced allergic contact dermatitis model in MSK1 ⁄ 2 knockout mice and wild-type mice. MSK1 ⁄ 2 knockout mice were demonstrated to have significantly increased inflammation compared with wild-type mice. This was measured by an increased ear thickness, elevated infiltration of neutrophils in the skin and increased inflammatory histological changes. Furthermore, we found significantly elevated levels of the proinflammatory cytokines Tumor necrosis factor-a (TNF-a), IL-1b and IL-6 at both mRNA and protein levels in MSK1 ⁄ 2 knockout mice compared with wild-type mice after oxazolone treatment. In addition, the mRNA expression of the chemokine Thymus and activation regulated chemokine (TARC) was demonstrated to be significantly elevated in oxazolone-treated MSK1 ⁄ 2 knockout mice compared with wild-type mice. The increased expression of TARC was paralleled by increased infiltration of cells positive for the TARC receptor, CCR4, in the dermis of MSK1 ⁄ 2 knockout mice. Our results indicate that MSK1 ⁄ 2 are involved in the activation of feedback mechanisms that dampen oxazolone-induced skin inflammation.

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CREB1 activation promotes human papillomavirus oncogene expression and cervical cancer cell transformation

Patterson

Morgan

et al. 2023

Journal of Medical Virology

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Human papillomaviruses (HPVs) infect the oral and anogenital mucosa and can cause cancer. The high‐risk (HR)‐HPV oncoproteins, E6 and E7, hijack cellular factors to promote cell proliferation, delay differentiation and induce genomic instability, thus predisposing infected cells to malignant transformation. cAMP response element (CRE)‐binding protein 1 (CREB1) is a master transcription factor that can function as a proto‐oncogene, the abnormal activity of which is associated with multiple cancers. However, little is known about the interplay between HPV and CREB1 activity in cervical cancer or the productive HPV lifecycle. We show that CREB is activated in productively infected primary keratinocytes and that CREB1 expression and phosphorylation is associated with the progression of HPV+ cervical disease. The depletion of CREB1 or inhibition of CREB1 activity results in decreased cell proliferation and reduced expression of markers of epithelial to mesenchymal transition, coupled with reduced migration in HPV+ cervical cancer cell lines. CREB1 expression is negatively regulated by the tumor suppressor microRNA, miR‐203a, and CREB1 phosphorylation is controlled through the MAPK/MSK pathway. Crucially, CREB1 directly binds the viral promoter to upregulate transcription of the E6/E7 oncogenes, establishing a positive feedback loop between the HPV oncoproteins and CREB1. Our findings demonstrate the oncogenic function of CREB1 in HPV+ cervical cancer and its relationship with the HPV oncogenes.

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MSK regulate TCR‐induced CREB phosphorylation but not immediate early gene transcription

Cited by 26 publications

References 49 publications

ERK5 regulation in naïve T‐cell activation and survival

ERK5 regulation in naïve T‐cell activation and survival

The role of mitogen‐ and stress‐activated protein kinase 1 and 2 in chronic skin inflammation in mice

CREB1 activation promotes human papillomavirus oncogene expression and cervical cancer cell transformation

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