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Genomic organization and regulation of the human orexin (hypocretin) receptor 2 gene : identification of alternative promoters
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Chen, Jing and Randeva, Harpal S. (2010) Genomic organization and regulation of the human orexin (hypocretin) receptor 2 gene : identification of alternative promoters. Biochemical Journal, Vol.427 (No.Part 3). pp. 377-390. doi:10.1042/BJ20091755 ISSN 0264-6021.
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Official URL: http://dx.doi.org/10.1042/BJ20091755
Abstract
Orexins (hypocretins), acting via their receptors, are involved in the control of feeding behaviour, sleep, arousal and energy homoeostasis. However, regulation of the human orexin receptor 2 (hOX2R) gene remains unknown. We have identified four transcripts arising from alternative splicing from three exons. These exon 1 variants were designated exons 1A, 1B and 1C on the basis of their 5'-3' order. RT (reverse transcription) PCR demonstrates the differential expression in various human tissues. The alternative 5'-UTRs (untranslated regions) possessed by these isoforrns have different translational efficiencies, which regulate the level of protein expression. In the present study, we have demonstrated that the hOX2R gene is regulated by two promoters and the novel transcripts are regulated by the distal promoter located upstream of exon 1A. We have demonstrated that the AP-1 (activator protein 1) motif is critical for sustaining the basal activity of distal promoter. Analysis of the proximal promoter revealed the region regulating promoter activity contained putative binding elements including those for CREB (cAMP-response-element-binding protein), GATA-2 and Oct-1. Using the chromatin immunoprecipitation assay, we demonstrated that CREB, GATA-2 and Oct-1 transcription factors bind to these critical regulatory promoter elements. Mutational studies suggested that these motifs functioned independently, but have a compound effect regulating hOX2R gene transcription. Furthermore, proximal promoter activity is enhanced by both PKA (protein kinase A) and PKC (protein kinase C) pathway activation, via binding of CREB and GATA-2 transcription factors. In conclusion, we have demonstrated that expression of hOX2R is regulated by a complex involving a proximal PKA/PKC-regulated promoter and a distal promoter regulating tissue-specific expression of alternative transcripts which in turn post-transcriptionally regulate receptor levels.
| Item Type: | Journal Article | ||||
|---|---|---|---|---|---|
| Subjects: | Q Science > QD Chemistry | ||||
| Divisions: | Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences > Translational & Experimental Medicine > Metabolic and Vascular Health (- until July 2016) Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School |
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| Journal or Publication Title: | Biochemical Journal | ||||
| Publisher: | Portland Press | ||||
| ISSN: | 0264-6021 | ||||
| Official Date: | 1 May 2010 | ||||
| Dates: |
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| Volume: | Vol.427 | ||||
| Number: | No.Part 3 | ||||
| Number of Pages: | 14 | ||||
| Page Range: | pp. 377-390 | ||||
| DOI: | 10.1042/BJ20091755 | ||||
| Status: | Peer Reviewed | ||||
| Publication Status: | Published | ||||
| Access rights to Published version: | Restricted or Subscription Access | ||||
| Funder: | General Charities of the City of Coventry, British Heart Foundation | ||||
| Grant number: | PG/03/131/15192 |
Data sourced from Thomson Reuters' Web of Knowledge
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