Unimpaired Thymic and Peripheral T Cell Death in Mice Lacking the Nuclear Receptor NGFI-B (Nur77)

Lee, Stephen; Wesselschmidt, Robin L.; Linette, Gerald P.; Kanagawa, Osami; Russell, John H.; Milbrandt, Jeffrey

doi:10.1126/science.7624775

Cited by 260 publications

(212 citation statements)

References 23 publications

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“…Transgenic expression of a dominant negative Nur77 protein, which can inhibit both Nur77 and Nor-1, does antagonize negative selection. 75,76 Therefore, it has been hypothesized that there may be redundancies between the family members. How Nur77 can induce apoptosis is still unclear, but one proposed mechanism is that upon TCR stimulation Nur77 is translocated from the nucleus to the mitochondria where it interacts with BCL-2 inducing a conformational change that converts BCL-2 into a proapoptotic molecule.…”

Section: Thymocyte Negative Selectionmentioning

confidence: 99%

Apoptosis in the development of the immune system

Opferman

2007

Cell Death Differ

118

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Apoptosis is a conserved genetic program critical for the development and homeostasis of the immune system. During the early stages of lymphopoiesis, growth factor signaling is an essential regulator of homeostasis by regulating the survival of lymphocyte progenitors. During differentiation, apoptosis ensures that lymphocytes express functional antigen receptors and is essential for eliminating lymphocytes with dangerous self-reactive specificities. Many of these critical cell death checkpoints during immune development are regulated by the BCL-2 family of proteins, which is comprised of both pro-and antiapoptotic members, and members of the tumor necrosis factor death receptor family. Aberrations in the expression or function of these cell death modulators can result in pathological conditions including immune deficiency, autoimmunity, and cancer. This review will describe how apoptosis regulates these critical control points during immune development.

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Section: Thymocyte Negative Selectionmentioning

confidence: 99%

Apoptosis in the development of the immune system

Opferman

2007

Cell Death Differ

118

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“…NGFI-B KO mice were developed by the group of Dr Milbrandt at the University of Washington (St Louis, Missouri, USA) . They are healthy and reproduce normally (Crawford et al, 1995;Lee et al, 1995). They were produced in a mixed background and have been backcrossed into the C57BL/6 strain for at least 10 generations to reduce background heterogeneity (Jeff Milbrandt, personal communication).…”

Section: Experimental Procedures Animal Care and Treatmentsmentioning

confidence: 99%

The Transcription Factor NGFI-B (Nur77) and Retinoids Play a Critical Role in Acute Neuroleptic-Induced Extrapyramidal Effect and Striatal Neuropeptide Gene Expression

Éthier

Beaudry

St-Hilaire

et al. 2003

Neuropsychopharmacol

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Despite extensive investigation, the cellular mechanisms responsible for neuroleptic actions remain elusive. We have previously shown that neuroleptics modulated the expression of some members of the ligand-activated transcription factors (nuclear receptors) including the nerve-growth factor inducible gene B (NGFI-B or Nur77) and retinoid X receptor (RXR) isoforms. Using genetic and pharmacological approaches, we investigated the role of NGFI-B and retinoids in acute behavioral and biochemical responses to dopamine antagonists. NGFI-B knockout (KO) mice display a profound alteration of haloperidol-induced catalepsy and striatal neuropeptide gene expression. Haloperidol-induced increase of striatal enkephalin mRNA is totally abolished in NGFI-B KO mice whereas the increase of neurotensin mRNA expression is reduced by 50%. Interestingly, catalepsy induced by raclopride, a specific dopamine D 2 /D 3 antagonist is completely abolished in NGFI-B-deficient mice whereas the cataleptic response to SCH 23390, a dopamine D 1 agonist, is preserved. Accordingly, the effects of haloperidol on striatal c-fos, Nor-1, and dynorphin mRNA expression are also preserved in NGFI-B-deficient mice. The cataleptic response and the increase of enkephalin mRNA expression induced by haloperidol can also be suppressed by administration of retinoid ligands 9-cis retinoic acid and docosahexaenoic acid. In addition, we demonstrate that haloperidol enhances colocalization of NGFI-B and RXRg1 isoform mRNAs, suggesting that both NGFI-B and a RXR isoform are highly coexpressed after haloperidol administration. Our data demonstrate, for the first time, that NGFI-B and retinoids are actively involved in the molecular cascade induced by neuroleptic drugs.

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“…Based on overexpression transgenics, nur77 has been suggested to regulate T-cell apoptosis [36]. Knockout mice for nur77 do not, however, exhibit a known T-cell phenotype [37] possibly due to functional compensation by nor1 [38].…”

Section: Introductionmentioning

confidence: 99%

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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Unimpaired Thymic and Peripheral T Cell Death in Mice Lacking the Nuclear Receptor NGFI-B (Nur77)

Cited by 260 publications

References 23 publications

Apoptosis in the development of the immune system

Apoptosis in the development of the immune system

The Transcription Factor NGFI-B (Nur77) and Retinoids Play a Critical Role in Acute Neuroleptic-Induced Extrapyramidal Effect and Striatal Neuropeptide Gene Expression

ERK5 regulation in naïve T‐cell activation and survival

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