CREB-binding protein activation by presenilin 1 but not by its M146L mutant.
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 1 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 1 may be involved in the disease process. We have shown that wild-type presenilin 1 stimulates the transcriptional activity ability of CREB-binding protein whereas presenilin 1 M146L mutant did not produce such an effect. The activation of CREB-binding protein by wild-type presenilin 1 involves the PI 3-kinase, p38 mitogen-activated protein kinase (MAPK) and p42/p44 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 1 and not by its M146L mutant, and suggests a mechanism in which mutation of presenilin 1 may lead to neurodegeneration.
Francis
Yitshak I
YI
Medical Molecular Biology Unit, Institute of Child Health, University College London, UK. Y.Francis@ich.ucl.ac.uk
Stephanou
Anastasis
A
Latchman
David S
DS
D000818:Animals; D050882:CREB-Binding Protein / Q000378:metabolism*; D002461:Cell Line, Transformed; D004789:Enzyme Activation / Q000235:genetics; D005455:Fluorescent Antibody Technique / Q000379:methods; D007930:Leucine / Q000235:genetics*; D008156:Luciferases / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics*; D008715:Methionine / Q000235:genetics*; D016296:Mutagenesis / Q000502:physiology; D009154:Mutation; D053764:Presenilin-1; D051381:Rats; D014162:Transfection / Q000379:methods
D008565:Membrane Proteins; D053764:Presenilin-1; D008715:Methionine; D008156:Luciferases; D050882:CREB-Binding Protein; D007930:Leucine