Regulation of the MEF2 Family of Transcription Factors by p38

Zhao, Ming; New, Liguo; Kravchenko, Vladimir V.; Kato, Yasuhiro; Gram, Hermann; Padova, Franco Di; Olson, Eric N.; Ulevitch, Richard J.; Han, Jiahuai

doi:10.1128/mcb.19.1.21

Cited by 411 publications

(382 citation statements)

References 48 publications

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“…It is possible that while ERK5 may regulate MEF2 in some cell lines, in T cells another putative kinase may play this role. One possibility would be p38a, which can also phosphorylate MEF2 transcription factors [47] and is activated downstream of the TCR [48]. Cell type differences in nur77 transcription have also been reported before.…”

Section: Discussionsupporting

confidence: 53%

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: Discussionsupporting

confidence: 53%

ERK5 regulation in naïve T‐cell activation and survival

et al. 2008

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“…50 A dominantnegative form of p38 MAPK and GFP control vector were kindly provided by Dr. J Han. 51,52 AdVs were amplified and titrated following standard methods. To infect cerebrocortical cultures with minimal toxicity, AdVs were used at a multiplicity of infection (MOI) of 10, as described recently.…”

Section: Methodsmentioning

confidence: 99%

HIV-1 coreceptors CCR5 and CXCR4 both mediate neuronal cell death but CCR5 paradoxically can also contribute to protection

et al. 2006

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The chemokine receptors CCR5 and CXCR4 serve, in addition to CD4, as coreceptors for human immunodeficiency virus-1 (HIV-1), and infection with HIV-1 can cause dementia. In brain-derived cells, HIV-1 envelope glycoprotein gp120 initiates a signaling cascade that involves p38 mitogen-activated protein kinase and leads to neuronal cell death. Using mixed neuronal/glial cultures from rats and mice genetically deficient in one or both HIV coreceptors, we show here that CCR5, CXCR4 or both can mediate HIV/ gp120 neurotoxicity depending on the viral strain. Paradoxically, we also found evidence for a CCR5-mediated neuroprotective pathway. We identify protein kinase Akt/PKB as an essential component of this pathway, which can be triggered by the CCR5 agonists macrophage inflammatory protein-1b and regulated-and-normal-T-cell-expressed-and-secreted. Moreover, these CCR5 ligands prevent neuronal cell death induced by stromal cell-derived factor-1, a CXCR4 agonist. Both neurons and glia coexpress CXCR4 and CCR5. Ca 2 þ imaging experiments demonstrate that engagement of CCR5 prevents CXCR4-triggered increases in intracellular free Ca 2 þ . This finding suggests that CCR5 ligands can protect neurons at least, in part, by modulating CXCR4-mediated toxicity through heterologous desensitization.

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“…Many transcription factors encompassing a broad range of action have been shown to be phosphorylated and subsequently activated by p38. Examples include activating transcription factor 1, 2 & 6 (ATF-1/2/6), SRF accessory protein (Sap1), CHOP (growth arrest and DNA damage inducible gene 153, or GADD153), p53, C/EBPβ, myocyte enhance factor 2C (MEF2C), MEF2A, MITF1, DDIT3, ELK1, NFAT, and high mobility group-box protein 1 (HBP1) [17,55,[66][67][68][69][70][71][72][73][74][75][76]] . An important cis-element, AP-1 appears to be influenced by p38 through several different mechanisms.…”

Section: Transcription Factors Activated By P38mentioning

confidence: 99%

“…An important cis-element, AP-1 appears to be influenced by p38 through several different mechanisms. ATF-2 is known to form heterodimers with Jun family transcription factors thereby directly associating with the AP-1 binding site [71]. Another possible mechanism comes from the observation that a component of AP-1 is c-fos.…”

Section: Transcription Factors Activated By P38mentioning

confidence: 99%

Activation and signaling of the p38 MAP kinase pathway

2005

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The family members of the mitogen-activated protein (MAP) kinases mediate a wide variety of cellular behaviors in response to extracellular stimuli. One of the four main sub-groups, the p38 group of MAP kinases, serve as a nexus for signal transduction and play a vital role in numerous biological processes. In this review, we highlight the known characteristics and components of the p38 pathway along with the mechanism and consequences of p38 activation. We focus on the role of p38 as a signal transduction mediator and examine the evidence linking p38 to inflammation, cell cycle, cell death, development, cell differentiation, senescence and tumorigenesis in specific cell types. Upstream and downstream components of p38 are described and questions remaining to be answered are posed. Finally, we propose several directions for future research on p38.

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Regulation of the MEF2 Family of Transcription Factors by p38

Cited by 411 publications

References 48 publications

ERK5 regulation in naïve T‐cell activation and survival

ERK5 regulation in naïve T‐cell activation and survival

HIV-1 coreceptors CCR5 and CXCR4 both mediate neuronal cell death but CCR5 paradoxically can also contribute to protection

Activation and signaling of the p38 MAP kinase pathway

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