Regulated control by granulocyte-macrophage colony-stimulating factor AU-rich element during mouse embryogenesis

Houzet, Laurent; Morello, Dominique; Defrance, P; Mercier, Pascale; Huez, Georges; Kruys, Véronique

doi:10.1182/blood.v98.5.1281

Cited by 14 publications

(10 citation statements)

References 31 publications

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“…Accordingly, we hypothesize that AREs within the 3′UTR of cytokine mRNAs limit translation in self-reactive T cells, a conclusion supported by numerous in vitro studies demonstrating that AREs promote decay and/or translational arrest of cytokine transcripts, and by the phenotypes of mice lacking AREs in the UTRs of TNF-α and GM-CSF, which exhibit aberrant cytokine production and severe autoimmune disease (Carballo et al, 1998; Garcia-Sanz and Lenig, 1996; Han et al, 1990; Houzet et al, 2001; Kontoyiannis et al, 1999; Kruys et al, 1989; Taylor et al, 1996). However, it should be noted that ARE-independent mechanisms are also likely to influence cytokine production in this setting.…”

Section: Discussionmentioning

confidence: 83%

Posttranscriptional Silencing of Effector Cytokine mRNA Underlies the Anergic Phenotype of Self-Reactive T Cells

et al. 2011

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SUMMARY Self-reactive T cell clones that escape negative selection are either deleted or rendered functionally unresponsive (anergic), thus preventing them from propagating host tissue damage. By using an in vivo model, we investigated molecular mechanisms for T cell tolerance, finding that despite a characteristic inability to generate effector cytokine proteins, self-reactive T cells express large amounts of cytokine mRNAs. This disconnect between cytokine message and protein was not observed in T cells mounting productive responses to foreign antigens but, instead, was seen only in those responding to self, where the block in protein translation was shown to involve conserved AU-rich elements within cytokine 3′UTRs. These studies reveal that translation of abundant cytokine mRNAs is limited in self-reactive T cells and, thus, identify posttranscriptional silencing of antigen-driven gene expression as a key mechanism underlying the anergic phenotype of self-reactive T cells.

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Section: Discussionmentioning

confidence: 83%

Posttranscriptional Silencing of Effector Cytokine mRNA Underlies the Anergic Phenotype of Self-Reactive T Cells

et al. 2011

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“…With only some of the possible isoforms present in a given cell, of all the possible controls only the few permitted by this selection will operate in this cell. This has been well demonstrated, e.g., for G protein ␣-subunits in the different cells of human fetal adrenal gland (30) or for AU-rich element (ARE) binding proteins that regulate the stability and translation of mRNA in embryos (142).…”

Section: Conclusion On Physiological Relevance Of Reported Effectsmentioning

confidence: 95%

Cross signaling, cell specificity, and physiology

Dumont¹,

Dremier²,

Pirson³

et al. 2002

American Journal of Physiology-Cell Physiology

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Dumont, J. E., S. Dremier, I. Pirson, and C. Maenhaut. Cross signaling, cell specificity, and physiology. Am J Physiol Cell Physiol 283: C2-C28, 2002; 10.1152/ajpcell.00581.2001.-The literature on intracellular signal transduction presents a confusing picture: every regulatory factor appears to be regulated by all signal transduction cascades and to regulate all cell processes. This contrasts with the known exquisite specificity of action of extracellular signals in different cell types in vivo. The confusion of the in vitro literature is shown to arise from several causes: the inevitable artifacts inherent in reductionism, the arguments used to establish causal effect relationships, the use of less than adequate models (cell lines, transfections, acellular systems, etc.), and the implicit assumption that networks of regulations are universal whereas they are in fact cell and stage specific. Cell specificity results from the existence in any cell type of a unique set of proteins and their isoforms at each level of signal transduction cascades, from the space structure of their components, from their combinatorial logic at each level, from the presence of modulators of signal transduction proteins and of modulators of modulators, from the time structure of extracellular signals and of their transduction, and from quantitative differences of expression of similar sets of factors.

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“…It was the first to be associated with the control of mRNA stability (1,17). The physiological importance of the ARE in the control of GM-CSF gene expression was demonstrated in transgenic mice bearing GM-CSF gene constructs lacking the ARE that presented severe hematopoietic disorders (18). The control of translation by the GM-CSF ARE is much less documented.…”

mentioning

confidence: 99%

In Vivo Studies of Translational Repression Mediated by the Granulocyte-Macrophage Colony-stimulating Factor AU-rich Element

Grosset

Boniface

Duchez

et al. 2004

Journal of Biological Chemistry

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The AU-rich element (ARE) controls the turnover of many unstable mRNAs and their translation. The granulocyte-macrophage colony-stimulating factor (GM-CSF) ARE is known to be a destabilizing element, but its role in translation remains unclear. Here we studied in vivo the role of the GM-CSF ARE on the mRNA and protein expressions of an enhanced green fluorescent protein reporter gene. The GM-CSF ARE had a repressor effect on translation independently of its effect on mRNA levels. In the context of an internal ribosome entry site, the GM-CSF ARE still repressed translation but was no longer functional as a destabilizing element. Gel retardation assays showed that poly(A)-binding protein is displaced from the poly(A) tail when the ARE is present in the 3-untranslated region. These data suggest that the GM-CSF ARE controls translation and mRNA decay by interfering with poly(A)-binding protein-mediated mRNA circularization.The mechanisms of post-transcriptional regulation at the level of mRNA degradation and translation are of importance in the control of gene expression, with the 3Ј-untranslated region (UTR) 1 central in this process (1). The adenosine uridine-rich element (ARE) is the most common regulatory determinant found in the 3Ј-UTR of many unstable mRNAs, and several types have been described (1).The ARE induces rapid mRNA turnover by first triggering poly(A) shortening, then inducing both 5Ј-end decapping and RNA body degradation by either 5Ј and 3Ј exonuclease complexes (1-4). Recent data also suggest involvement of the ubiquitin-dependent pathway in the control of ARE-mediated mRNA turnover (5). Whereas the ARE-mediated cap-dependent deadenylation model is largely accepted in yeast, it remains to be demonstrated in mammalian cells. For this reason,

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Regulated control by granulocyte-macrophage colony-stimulating factor AU-rich element during mouse embryogenesis

Cited by 14 publications

References 31 publications

Posttranscriptional Silencing of Effector Cytokine mRNA Underlies the Anergic Phenotype of Self-Reactive T Cells

Posttranscriptional Silencing of Effector Cytokine mRNA Underlies the Anergic Phenotype of Self-Reactive T Cells

Cross signaling, cell specificity, and physiology

In Vivo Studies of Translational Repression Mediated by the Granulocyte-Macrophage Colony-stimulating Factor AU-rich Element

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