Methylation of an Immediate-Early Inducible Gene as a Mechanism for B Cell Tolerance Induction

Seyfert, V L; McMahon, Steven B.; Glenn, William D.; Yellen, Amy; Sukhatme, Vikas P.; Cao, Xinmin; Monroe, John G.

doi:10.1126/science.2237429

Cited by 73 publications

(46 citation statements)

References 27 publications

(26 reference statements)

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“…We have chosen the induction of the Krox-24 gene as an endpoint because the activation of MAPK has been correlated with an increase in its transcription [38] and also because its induction is a ubiquitous correlate of mitogenic stimulation [39]. Krox-24 expression is independent of protein synthesis and appears within minutes of mitogenic stimulation [40,41]. Our results showed a massive accumulation of Krox-24 protein on stimulation with NT in both CHO-hNTR and HT29 cells.…”

Section: Ntr Stimulation Induces Krox-24 Gene Expressionmentioning

confidence: 99%

Activation of mitogen-activated protein kinase couples neurotensin receptor stimulation to induction of the primary response gene Krox-24

Poinot-Chazel

Portier

Bouaboula

et al. 1996

Biochemical Journal

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Neurotensin (NT) is a neuropeptide that is important in a variety of biological processes such as signal transduction and cell growth. NT effects are mediated by a single class of cell-surface receptors, known as neurotensin receptors (NTRs), which exhibit structural features of the G-protein-coupled receptors superfamily. We investigated NTR signalling properties with Chinese hamster ovary (CHO) cells stably transformed with human NTR (hNTR). First, we showed that NTR stimulation by NT induced the activation of the mitogen-activated protein kinases (MAPKs) in time- and dose-dependent manners. Both p42 and p44 MAPK isoforms were retarded in gel-shift assays, which was consistent with their activation by phosphorylation. In addition we showed that NT caused a prolonged activation of MAPK as measured by in-gel kinase assay. Secondly, we demonstrated that NT induced the expression of the growth-related gene Krox-24 at the protein level, as assessed by Western-blot analysis, and at the transcriptional level, as demonstrated in CHO cells transfected with hNTR and a reporter gene for Krox-24. Activation of MAPK and induction of Krox-24 were both prevented by the NTR antagonist SR 48692, confirming the specific action on NTR. Furthermore we observed coupling of NTR to a mitogenic pathway and Krox-24 induction in the human adenocarcinoma cell line HT29, which naturally expresses NTRs. Considering coupling pathways between NTR stimulation and MAPK activation, we observed a partial inhibition by pertussis toxin (PTX) and a complete blockade by the protein kinase C (PKC) inhibitor GF 109203X. Taken together, these results suggest that (1) stimulation of NTR activates the MAPK pathway by mechanisms involving dual coupling to both PTX-sensitive and PTX-insensitive G-proteins as well as PKC activation, and (2) these effects are associated with the induction of Krox-24, which might be a target of MAPK effector.

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Section: Ntr Stimulation Induces Krox-24 Gene Expressionmentioning

confidence: 99%

Activation of mitogen-activated protein kinase couples neurotensin receptor stimulation to induction of the primary response gene Krox-24

Poinot-Chazel

Portier

Bouaboula

et al. 1996

Biochemical Journal

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“…Alternatively, perhaps the IEG proteins present basally are not active, and their activation requires post-translational modifications (phosphorylation, demethylation, etc.) (Seyfert et al, 1990). A previous report suggested that Zif268 may play a role in spontaneously maintaining the inhibitory output of GABAergic neurons in the striatum (Ishida et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Differential expression of Fos and Zif268 in the nigrostriatal system after methamphetamine administration in a rat model of Parkinson's disease

Ishida

Kawai

Magata

et al. 2008

Synapse

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The goal of this study was to examine the topological specificity of methamphetamine-induced activation of the immediate-early gene proteins, Fos and Zif268, in the nigrostriatal system in a unilateral 6-hydroxydopamine (6-OHDA) rat model of Parkinson's disease with or without intrastriatal grafts of fetal ventral mesencephalon. Methamphetamine (3 mg/kg, i.p.) induced Fos-like immunoreactivity (FLI) dominantly in the striatum and the globus pallidus (GP) on the intact side as well as in the substantia nigra pars reticulata (SNr) on the lesioned side in the 6-OHDA rats. Lower levels of methamphetamine-induced FLI in the striatum and GP on the lesioned side were restored by intrastriatal grafts which could completely suppress the methamphetamine-induced rotation. In the striatum, a similar tendency could be observed between Fos and Zif268 immunoreactivity following methamphetamine. However, sparse immunoreactivity of Zif268 could be detected in the GP and SNr on both sides in the 6-OHDA rats. Intrastriatal grafts had little influence on Zif268 expression in these two regions. The differential expression of Fos and Zif268 was observed among the three regions of the nigrostriatal system following methamphetamine in the 6-OHDA rats. This may suggest that Fos and Zif268 therefore possess gene-specific and region-specific functions in the basal ganglia nuclei. Synapse 62: 920-926, 2008. V

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“…Seyfert et al [59] have provided an interested suggestion. B cell lines representative of mature and immature B cells exist, and both can have their Ig receptors cross-linked by anti-p heavy-chain antibodies, but whereas this results in a positive growth response in the mature B cell line, a negative, growth-inhibitory signal is delivered to the immature line resulting in eventual cell death.…”

Section: Clonal Abortion and Clonal Anergy In B Lymphocyte Tolerancementioning

confidence: 99%

Molecular and cellular aspects of immunologic tolerance

Nossal

1991

European Journal of Biochemistry

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This review seeks to explain the most exciting recent data concerning the nature of self/non-self discrimination by the immune system in a manner accessible to a biochemical readership. The nature of recognition in the two great lymphocyte families, B cells and T cells, is described with special emphasis on the nature of the ligands recognized by each. The history of the field of immunologic tolerance is surveyed, as are the key experiments on conventional mice which provided a conceptual framework. This suggested that tolerance was essentially due to 'holes' in the recognition repertoires of both the T and B cell populations so that lymphocytes competent to react to self antigens were not part of the immunologic dictionary. There were essentially two ways to achieve this situation. On the one hand, self antigens might 'catch' developing lymphocytes early in their ontogeny and delete the cell, a process of clonal abortion. On the other hand, self antigens might signal lymphocytes (particularly immature cells) in a negative manner, reducing or abolishing their capacity for later responses, without causing death. This process is referred to as clonal anergy. Evidence for both processes exists.Special emphasis is placed on a wave of experimentation beginning in 1988 which imaginatively uses transgenic mouse technology to study tolerance. Transgenic manipulations can produce mice which synthesize foreign antigens in a constitutive and/or inducible manner, sometimes only in specific locations; mice which possess T or B lymphocytes almost all expressing a given receptor of known specificity; and mice which are an immunologic time bomb in that the antigen is present and so too are lymphocytes all endowed with receptors for that antigen. These experiments have vindicated the possibility of both clonal abortion and clonal anergy in both T and B cell populations, the choice of which phenomenon occurs depending on a number of operational circumstances. For T cell tolerance, clonal abortion occurs if the self antigenic determinant concerned is present within the thymus; if not, clonal anergy is more likely. For B cell tolerance, the strength of the negative signal and therefore the choice between abortion and anergy depends on the molar concentration of the self antigen, the capacity for multivalent presentation to a B cell, and the affinity of the B cell's receptor for the antigen in question. Some B cells with low affinity for self antigens certainly escape censorship and remain capable of secreting low affinity anti-self antibodies, which however do no harm. Mechanisms which prevent the emergence of hypermutated, high-affinity anti-self B cells are discussed.Lt is an honour and also a considerable challenge to be asked to summarize an essentially immunological topic, and an important and rapidly moving one, for a biochemical readership. The task is worthwhile because biochemistry and molecular biology have revolutionized immunology over the last quarter century, and because immunologic tolerance remains the single most i...

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Methylation of an Immediate-Early Inducible Gene as a Mechanism for B Cell Tolerance Induction

Cited by 73 publications

References 27 publications

Activation of mitogen-activated protein kinase couples neurotensin receptor stimulation to induction of the primary response gene Krox-24

Activation of mitogen-activated protein kinase couples neurotensin receptor stimulation to induction of the primary response gene Krox-24

Differential expression of Fos and Zif268 in the nigrostriatal system after methamphetamine administration in a rat model of Parkinson's disease

Molecular and cellular aspects of immunologic tolerance

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