The Selective Alzheimer's Disease Indicator-1 Gene (Seladin-1/DHCR24) Is a Liver X Receptor Target Gene
| Autor: | Thomas P. Burris, Pamela M. Rogers, Yongjun Wang, Chen Su, Qi Shen, Keith R. Stayrook, Gábor Varga, Sunil Nagpal |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
Oxidoreductases Acting on CH-CH Group Donors
Response element Receptors Cytoplasmic and Nuclear Nerve Tissue Proteins Response Elements Cell Line Mice Alzheimer Disease Gene expression Amyloid precursor protein Animals Humans Liver X receptor Liver X Receptors Skin Mice Knockout Pharmacology Reporter gene biology HEK 293 cells Brain Orphan Nuclear Receptors Molecular biology Introns DNA-Binding Proteins Nuclear receptor biology.protein Molecular Medicine lipids (amino acids peptides and proteins) Amyloid precursor protein secretase |
| Zdroj: | Molecular Pharmacology. 74:1716-1721 |
| ISSN: | 1521-0111 0026-895X |
| DOI: | 10.1124/mol.108.048538 |
| Popis: | The nuclear hormone receptors liver X receptor (LXR) and LXR function as physiological receptors for oxidized cholesterol metabolites (oxysterols) and regulate several aspects of cholesterol and lipid metabolism. Seladin-1 was originally identified as a gene whose expression was down-regulated in regions of the brain associated with Alzheimer’s disease. Seladin-1 has been demonstrated to be neuroprotective and was later characterized as 3-hydroxysterol-24 reductase (DHCR24), a key enzyme in the cholesterologenic pathway. Seladin-1 has also been shown to regulate lipid raft formation. In a whole genome screen for direct LXR target genes, we identified an LXR occupancy site within the second intron of the Seladin-1/DHCR24 gene. We characterized a novel LXR response element within the second intron of this gene that is able to confer LXR-specific ligand responsiveness to reporter gene in both HepG2 and human embryonic kidney 293 cells. Furthermore, we found that Seladin-1/ DHCR24 gene expression is significantly decreased in skin isolated from LXR-null mice. Our data suggest that Seladin1/DHCR24 is an LXR target gene and that LXR may regulate lipid raft formation. Amyloid- (A) peptide accumulation in the central nervous system underlies the pathological process in Alzheimer’s disease (AD), and these peptides are formed from proteolytic cleavage of the amyloid precursor protein (APP), an integral membrane protein. -Secretase (BACE) and -secretase are the proteases responsible for cleaving the A peptide from APP on the amino and carboxyl termini, respectively. The Seladin-1 gene (Selective Alzheimer’s Disease Indicator-1) was originally identified based on its selective downregulation of expression in regions of the brain vulnerable to AD relative to normal brains (Greeve et al., 2000; Iivonen et al., 2002). In cell culture, increased Seladin-1 expression was |
| Databáze: | OpenAIRE |
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