| 研究概要 |
The research funded by this grant has resulted in several novel discoveries that give important insights into the mechanism by which zif268 gene expression is regulated by the activation of muscarinic acetylcholine receptors,in particular,concerning the role of the MAPK signaling cascade in this activation:1)Stimulation of PC12D cell with high concentrations of the muscarinic receptor agonists carbachol or oxotremorine results in the rapid stimulation of phosphotidylinolitol turnover and activation of MAPK and dramatic increases in zif268 mRNA levels. Activation of MAPK and zif268 gene expression are both largely inhibited by combined pretreatment with the PKC inhibitor bisindoylylmaleimide and the calcium chelator EGTA,suggesting that DAG and IP3 produced by activation of PLC may be the initial intracellular signaling molecules that mediate the activation of MAPK and increases in zif268 mRNA. 2)Stimulation of PC12D cells with low concentration of carbachol results in the activation of MAPK only and does not measurably stimulate phosphatidylinositol metabolism or increase levels of zif268 mRNA. THis result suggests that activation of MAPK is not sufficient for the activation of zif268,a quite unexpected conclusion since expression of the zif268 gene is controlled primarily by several serum response elements(SRE) lobated in the zif268 promoter and previous studies have provided storong evidence that the SRE is a final target of the MAPK signaling cascade. 3)Examination of the
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