Regulation of the Rat p75 Neurotrophin Receptor Promoter by GC Element Binding Proteins

doi:10.1006/bbrc.1996.1844

Biochemical and Biophysical Research Communications

Volume 229, Issue 2, 13 December 1996, Pages 565-570

https://doi.org/10.1006/bbrc.1996.1844 Get rights and content

Abstract

Human and rat p75 neurotrophin receptor genes contain four conserved GC elements within their proximal promoter regions. These motifs are potentially recognized by many transcription factors. Here, we show that this proximal region of the rat gene is responsible for basal promoter function in both neuronal and non-neuronal cells. Coexpression of Wilms’ tumor suppressor WT1 represses, whereas transcription factor Sp1 activates p75 promoter constructs in kidney cells. Furthermore, purified Sp1 protein binds with high affinity to p75 promoter elements as assayed by DNase I footprinting. These findings suggest an important role for the GC element binding proteins in the regulation of p75 promoter function.

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Citation Excerpt :
It has a DNA-binding domain composed of three Zn fingers [74]. Some of the targets of Sp1 are insulin-like growth factor receptor [75], the NMDA receptor [76] and the neurotrophin receptor [77]. Although Sp1 is present in mature tissues, its expression is enhanced 100-fold in differentiating cells suggesting that it plays a distinct role during cellular development [78].
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Regulation of low affinity neurotrophin receptor (p75<sup>NTR</sup>) by early growth response (Egr) transcriptional regulators
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The low affinity neurotrophin receptor p75^NTR is a multifunctional receptor with important roles in neurotrophin signaling, axon outgrowth, and oligodendroglia and neuron survival. It is transcriptionally regulated with spatial and temporal precision during nervous system development, injury and regeneration. Very little is known about how p75^NTR expression is dynamically regulated but it is likely to influence how p75^NTR signals in particular cellular contexts. Here, we identify the early growth response (Egr) transcriptional regulators, Egr1 and Egr3, as direct modulators of p75^NTR gene expression. Egr1 and Egr3 bind and transactivate the p75^NTR promoter in vitro and in vivo, using distinct response elements on the p75^NTR promoter. Consistent with these results, p75^NTR expression is greatly diminished in muscle spindle stretch receptors and in peripheral nerve Schwann cells in Egr gene deficient mice. Taken together, the results elucidate a novel mechanism whereby Egr proteins can directly modulate p75^NTR expression and signaling in vivo.
Context-dependent dysregulation of transcription by mutant huntingtin
2006, Journal of Biological Chemistry
Citation Excerpt :
Like many other Sp1-dependent promoters, the p75 NGFR promoter lacks TATA and CAAT elements and is GC-rich. The activity of the NGFR promoter is dependent on Sp1 (31) and inhibited by mutant htt (9, 12). Thus, we used the NGFR promoter as a tool to examine the effect of different htt fragments on Sp1-mediated transcription.
Huntington disease (HD) is an adult-onset neurodegenerative disease caused by expansion of a polyglutamine (poly(Q) tract in the N-terminal region of huntingtin (htt). Although the precise mechanisms leading to neurodegeneration in HD have not been fully elucidated, transcriptional dysregulation has been implicated in disease pathogenesis. In HD, multiple N-terminal mutant htt fragments smaller than the first 500 amino acids have been found to accumulate in the nucleus and adversely affect gene transcription. It is unknown whether different htt fragments in the nucleus can differentially bind transcription factors and affect transcription. Here, we report that shorter N-terminal htt fragments, which are more prone to misfolding and aggregation, are more competent to bind Sp1 and inhibit its activity. These effects can be reversed by Hsp40, a molecular chaperone that reduces the misfolding of mutant htt. Our results provide insight into the beneficial effects of molecular chaperones and suggest that context dependent transcriptional dysregulation may contribute to differential toxicity of various N-terminal htt fragments.
Sp1 as a target site for metal-induced perturbations of transcriptional regulation of developmental brain gene expression
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Differential gene expression is partially regulated by zinc finger proteins (ZFP) such as Sp1, which may be potential targets for perturbations by environmental metals. In this paper, we discuss the selective effects of lead (Pb) and other heavy metals on the in vitro and in vivo DNA-binding of Sp1, and the developmental expression of its target genes. We have found that the presence of Pb, Zn and Cd in a DNA-binding assay differentially modulated the binding of Sp1 to its specific DNA sequence, while Ca, Mg and Ba, did not. In PC12 cells, cultured in the presence of low concentrations of Pb, a premature enhancement of Sp1 DNA-binding was observed. Similarly, Sp1 DNA-binding in the cerebellum of Pb-exposed animals was shifted to the first week after birth, while the developmental profile of a non-ZFP, NF_kB, was not. Furthermore, selective premature peaks of myelin basic protein and proteolipid protein mRNA expression were observed to occur in a manner relative to the changes in Sp1 DNA-binding. Since these genes are high targets for Sp1, these data suggest that exposure to heavy metals may alter developmental gene expression and brain development through selective modulation of the transcriptional activity of Sp1.
MyoD and MEF2A mediate activation and repression of the p75(NGFR) gene during muscle development
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In an effort to clarify transient expression of the NGF low-affinity receptor p75^NGFRduring muscle development we have focused on the molecular mechanisms involved in the initiation and cessation of p75^NGFRgene expression. Using quiescent C3H10T1/2 fibroblast as a tool, we observed that induction of differentiation competence in MyoD-transfected 10T1/2 fibroblasts was accompanied by the initiation of p75^NGFRexpression. Moreover, we could show that the bHLH transcription factor MyoD itself is a powerful candidate for transcriptional activation of the p75^NGFRgene in muscle precursor cells. By means of MyoD-mutants we have found that both the amino terminus of the MyoD molecule as well as the bHLH-region are essential for transcriptional activity on the p75^NGFRpromoter. The fact that myocyte enhancer factor MEF2A inactivated MyoD-induced p75^NGFRpromoter activity strongly suggests that cell-specific regulation of the p75NGFR gene might be strictly dependent on the intracellular composition and balance of the appropriate bHLH-transcription factors and their modulators.
Gene expression of neurotrophins and their receptors in cultured rat vascular smooth muscle cells
1998, Biochemical and Biophysical Research Communications
Most previous researches on neurotrophins including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3) have focused on the nervous system, because their receptors are widely distributed in neuronal tissues. Recently, however, the participation of neurotrophins in inflammation and atherosclerosis has been proposed. Therefore, the gene expression of neurotrophins is now an urgent issue is to be investigated in nonneuronal tissues. Here, we evaluated the gene expression of neurotrophins and their receptors in rat cultured vascular smooth muscle cells (VSMCs) by the reverse transcriptase-polymerase chain reaction method. The transcripts of NGF, NT-3, and TrkC (high-affinity receptor for NT-3), and two BDNF alternative spliced transcript variants with exons 3 and 4 were clearly detected in VSMCs cultured under conventional culture conditions. The upregulation of mRNA levels for NGF, two BDNF variants with exons 1 and 2, low-affinity neurotrophin receptor, and high-affinity receptors, TrkA (for NGF) and TrkB (for BDNF), was observed in response to the treatment with serum and phorbol-ester following the serum-starvation. In contrast, the expression of NT-3 and TrkC genes was downregulated under these conditions. Co-expression of these factors and their receptors and the characteristic regulation of their gene transcriptions suggest that these factors play crucial roles in the function of VSMCs through an autocrine mechanism.

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¹: Present address: Department of Cell and Molecular Biology, Medical Nobel Institute, Karolinska Institutet, S-17177 Stockholm, Sweden.

²: Corresponding author. Fax: +358-9-191 8681. E-mail: [email protected].

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Regular ArticleRegulation of the Rat p75 Neurotrophin Receptor Promoter by GC Element Binding Proteins

Abstract

Regular Article
Regulation of the Rat p75 Neurotrophin Receptor Promoter by GC Element Binding Proteins