期刊
NEUROREPORT
卷 17, 期 9, 页码 917-921出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/01.wnr.0000220137.06542.a0
关键词
Alzheimer's disease; CREB-binding protein; mitogen-activated protein kinase; p38 MAPK; PI 3-kinase; presenilin 1
The transcriptional coactivator CREB-binding protein plays a key role in regulating gene expression in a number of different cell types. Recently, a report has suggested a link between CREB-binding protein and presenilins, which are mutated in many cases of early onset Alzheimer's disease. Thus, presenilin I and 2 double knockout mice showed reductions in CREB-binding protein levels and in cAMP response element-dependent gene expression in the cerebral cortex, which is likely to contribute to the subsequent neuronal degeneration. This suggests that the inactivation of CREB-binding protein caused by mutation in presenilin I may be involved in the disease process. We have shown that wild-type presenilin I stimulates the transcriptional activity ability of CREB-binding protein whereas presenilin I M146L mutant did not produce such an effect. The activation of CREB-binding protein by wildtype presenilin I involves the PI 3-kinase, p38 mitogen-activated protein kinase (MAPK) and p42/p,44 MAPK pathways and targets primarily the C terminus of CREB-binding protein. To our knowledge, this is the first report that shows regulation of CREB-binding protein activity by wild-type presenilin I and not by its M146L mutant, and suggests a mechanism in which mutation of presenilin I may lead to neurodegeneration.
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