Huntington's disease (HD) is a hereditary neurodegenerative disorder resulting from the expansion of a polyglutamine tract in the huntingtin protein. The expansion of cytosine-adenine-guanine repeats results in neuronal loss in the striatum and cortex. Mutant huntingtin (HTT) may cause toxicity via a range of different mechanisms. Recent studies indicate that impairment of wild-type HTT function may also contribute to HD pathogenesis. However, the mechanisms regulating HTT expression have not been well defined. In this study, we cloned 1,795 bp of the 5' flanking region of the human huntingtin gene (htt) and identified a 106-bp fragment containing the transcription start site as the minimal region necessary for promoter activity. Sequence analysis reveals several putative regulatory elements including Sp1, NF-κB, HIF, CREB, NRSF, P53, YY1, AP1, and STAT in the huntingtin promoter. We found functional Sp1 response elements in the huntingtin promoter region. The expression of Sp1 enhanced huntingtin gene transcription and the inhibition of Sp1-mediated transcriptional activation reduced huntingtin gene expression. These results suggest that Sp1 plays an important role in the regulation of the human huntingtin gene expression at the mRNA and protein levels. Our study suggests that the dysregulation of Sp1-mediated huntingtin transcription, combining with mutant huntingtin's detrimental effect on other Sp1-mediated downstream gene function, may contribute to the pathogenesis of HD.
[Show abstract][Hide abstract] ABSTRACT: P2X7 receptors are involved not only in physiological functions but also in pathological brain processes. Although an increasing
number of findings indicate that altered receptor expression has a causative role in neurodegenerative diseases and cancer,
little is known about how expression of P2rx7 gene is controlled. Here we reported the first molecular and functional evidence that Specificity protein 1 (Sp1) transcription
factor plays a pivotal role in the transcriptional regulation of P2X7 receptor. We delimited a minimal region in the murine
P2rx7 promoter containing four SP1 sites, two of them being highly conserved in mammals. The functionality of these SP1 sites was
confirmed by site-directed mutagenesis and Sp1 overexpression/down-regulation in neuroblastoma cells. Inhibition of Sp1-mediated
transcriptional activation by mithramycin A reduced endogenous P2X7 receptor levels in primary cultures of cortical neurons
and astrocytes. Using P2rx7-EGFP transgenic mice that express enhanced green fluorescent protein under the control of P2rx7 promoter, we found a high correlation between reporter expression and Sp1 levels in the brain, demonstrating that Sp1 is
a key element in the transcriptional regulation of P2X7 receptor in the nervous system. Finally, we found that Sp1 mediates
P2X7 receptor up-regulation in neuroblastoma cells cultured in the absence of serum, a condition that enhances chromatin accessibility
and facilitates the exposure of SP1 binding sites.
[Show abstract][Hide abstract] ABSTRACT: Huntington's disease (HD) is a signature polyglutamine disorder. An enduring theory of HD pathogenesis has involved dysregulation of transcription. Indeed, transcriptional regulatory proteins can be modulated to overcome cardinal features of HD-modeled mice, and efforts to move these into human studies are ongoing. Here, we discuss a unifying hypothesis emerging from these studies, which is that HD represents the pathological disruption of evolutionarily conserved adaptive gene programs to counteract oxidative stress, mitochondrial dysfunction and accumulation of misfolded proteins. Transcriptional dyshomeostasis of adaptive genes is further exacerbated by repression of genes involved in normal synaptic activity or growth factor signaling.
Drug discovery today 07/2014; 19(7). DOI:10.1016/j.drudis.2014.03.016 · 6.69 Impact Factor
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