Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neuron-restrictive silencer factor (NRSF, also termed REST) has been proposed to restrict expression of a set of genes to neurons by blocking their transcription in nonneuronal cells. The N-methyl-D-aspartate (NMDA) receptor subunit type I (NR1) gene contains a consensus sequence for the NRSF/REST binding site (NRSE/RE1). In this study, we evaluated the contribution of NRSF/REST to neuronal specificity of the NR1 gene. NR1 mRNA expression correlates with the absence of NRSF/REST binding activity, rather than expression of NRSF/REST protein, in several cell lines, suggesting that the absence of NRSF/REST-binding activity is necessary for the expression of the NR1 gene. HeLa cells, which do not express the NR1 gene, have NRSF/REST binding activity to the NR1 NRSE/RE1, resulting in inhibition of NR1 promoter activity. However, we also found that two nonneuronal cell lines (C6 glioma and P19 embryonal carcinoma) that lack NRSF/REST-binding activity, manifest only small amounts of NR1 mRNA compared to neuronal cell lines (PC12 pheochromocytoma and neuronally differentiated P19 cells). The enhancement of NR1 mRNA levels during neuronal differentiation of P19 cells is accompanied by an increase in NR1 promoter activity in an NRSF/REST-binding independent manner. Our results suggest therefore that the absence of NRSF/REST-binding activity is necessary but not sufficient for robust NR1 transcription in neuronal cells.
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PMID:Absence of binding activity of neuron-restrictive silencer factor is necessary, but not sufficient for transcription of NMDA receptor subunit type 1 in neuronal cells. 1064 Jun 75

Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive glial tumor that occurs in children. The extremely poor median and 5-year survival in children afflicted with DIPG highlights the need for novel biology-driven therapeutics. Here, we have implicated the chromatin remodeler and regulator of brain development called RE1 Silencing Transcription Factor (REST), in DIPG pathology. We show that REST protein is aberrantly elevated in at least 21% of DIPG tumors compared to normal controls. Its knockdown in DIPG cell lines diminished cell growth and decreased their tumorigenicity in mouse intracranial models. DIPGs are vascularized tumors and interestingly, REST loss in DIPG cells also caused a substantial decline in tumor vasculature as measured by a decrease in CD31 and VEGFR2 staining. These observations were validated in vitro, where a significant decline in tube formation by human umbilical vein endothelial cells (HUVEC) was seen following REST-loss in DIPG cells. Mechanistically, REST controlled the secretion of a pro-angiogenic molecule and ligand for VEGFR2 called Gremlin-1 (GREM-1), and was associated with enhanced AKT activation. Importantly, the decline in tube formation caused by REST loss could be rescued by addition of recombinant GREM-1, which also caused AKT activation in HUVECs and human brain microvascular endothelial cells (HBMECs). In summary, our study is the first to demonstrate autocrine and paracrine functions for REST in DIPG development. It also provides the foundation for future investigations on anti-angiogenic therapies targeting GREM-1 in combination with drugs that target REST-associated chromatin remodeling activities.
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PMID:REST upregulates gremlin to modulate diffuse intrinsic pontine glioma vasculature. 2943 75