Serum- and Glucocorticoid-Inducible Kinase 1 Enhances zif268 Gene Expression through the Mediation of SRF and CREB1 in Association with Spatial Memory Formation
| Autor: | Shiaw-Wei Tyan, 田孝威 |
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| Rok vydání: | 2008 |
| Druh dokumentu: | 學位論文 ; thesis |
| Popis: | 96 Serum- and glucocorticoid-inducible kinase 1 (SGK1) has been shown to play an important role in spatial memory formation, but the underlying molecular mechanism is not known. In the present study, the hypothesis that SGK1 regulates transcription of the immediate early gene zif268, a transcription factor that is essential for memory formation, was tested. The mechanism for SGK1-regulated zif268 expression in relation to the transcription factors, SRF, Elk-1, and CREB1, was also studied. Results revealed that transfection of the dominant negative mutant of SGK1, SGK1 S422A, to rat hippocampal CA1 area significantly decreased the mRNA level of zif268 induced by water maze learning. SGK1 was found to phosphorylate SRF at Ser73, Ser75 and Ser99, and phosphorylate CREB1 at Ser133. Inhibition of phosphorylation at these residues with alanine substitution significantly diminished SGK1-enhanced zif268 expression. SGK1 also phosphorylated Elk-1 at Ser159 and Thr160, but it did not affect SGK1-enhanced zif268 expression. Substitution of these residues with aspartate to mimic SGK1 phosphoryltion of Elk-1 decreased the transcriptional activity of Elk-1, suggesting that SGK1 may negatively regulate Elk-1. Moreover, phosphorylation of SGK1 at Ser422 was increased in rat hippocampal CA1 area after water maze learning, accompanied by increased phosphorylation of SRF at Ser99 and CREB1 at Ser133. These effects were antagonized by transfection of SGK1 S422A. These results suggest that SGK1 enhances zif268 expression through the mediation of SRF and CREB1. These signaling pathways are probably involved in spatial memory formation. |
| Databáze: | Networked Digital Library of Theses & Dissertations |
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