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Abstract

One of the pathological hallmarks of Alzheimerâ��s disease is the presence of fibrillar amyloid-�² deposits, which result from cleavage of the amyloid precursor protein. Understanding the regulatory mechanism of the amyloid precursor protein gene expression is crucial for comprehending the genesis and development of Alzheimerâ��s disease. The nucleic acid binding protein, Pur�±, is best characterized as a transcriptional factor (TF) with affinity to single-strand G/C-rich regions. In a previous study, we demonstrated that the Pur�± protein can downregulate amyloid pre-cursor protein (A�²PP) promoter activity, but the mechanism underlying this downregulation requires further investigation. To better understand this mechanism, we analyzed the characteristic of the A�²PP promoter and found that another transcriptional factor, namely Egr-1, can bind the A�²PP promoter and may exert transcriptional regulatory effects on A�²PP gene expression. Therefore, the interaction between these two transcriptional factors may explain the mechanism regulating A�²PP gene expression. The binding sites of Pur-�± and Egr- 1 on the A�²PP promoter 5â��-UTR were identified, and reporter plasmids in which the binding sites for Pur�± and Egr-1 were deleted were constructed. A luciferase assay was performed, and the results demonstrated that both Pur�± and Egr-1 lost their regulatory effects when these binding sites were deleted. The luciferase results also demonstrated that Pur�± can suppress the effects of Egr-1. The electrophoresis mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) assay results demonstrated that both Pur�± and Egr-1 can competently bind to the A�²PP promoter. The endogenous Egr-1 expression was disturbed with the HDAC inhibitor and suramin, and the Egr-1 expression level affected the A�²PP promoter activities and A�²PP gene expression. Pur�± can also suppress the endogenous expression of Egr-1. The mechanism through which Pur�± regulates A�²PP gene expression may involve its inter-action with Egr-1, which is a positive regulator of the A�²PP promoter. Because both TFs possess the binding sites in the A�²PP promoter 5â��-UTR and the position of these sites overlap, there may exist a displacement mechanism for these two TFs. In addition, Pur�± also suppresses the endogenous Egr-1 expression. All of these findings explain the mechanism through which Pur�± regulates A�²PP gene expression.

Biography

Jianqi Cui has completed his PhD in 1994 from Beijing Institute of Besic Medical Sciences and postdoctoral studies from Thomas Jefferson University. He is the professor of Biochemistry and molecular biology of Ningxia Medical University. He has published more than 50 papers in reputed journals and has been serving as a editor for Journal of Neurology and Neurosciences. His research spans areas including the cardiovascular diseases, breast cancer and neurology.

Email: bu_kan@yahoo.com