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キーワード:
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要旨:
Epigenetic processes, such as DNA methylation, and molecular chaperones,
including FK506-binding protein 51 (FKBP51), are independently
implicated in stress-related mental disorders and antidepressant drug
action. FKBP51 associates with cyclin-dependent kinase 5 (CDK5), which
is one of several kinases that phosphorylates and activates DNA
methyltransferase 1 (DNMT1). We searched for a functional link between
FKBP51 (encoded by FKBP5) and DNMT1 in cells from mice and humans,
including those from depressed patients, and found that FKBP51 competed
with its close homolog FKBP52 for association with CDK5. In human
embryonic kidney (HEK) 293 cells, expression of FKBP51 displaced FKBP52
from CDK5, decreased the interaction of CDK5 with DNMT1, reduced the
phosphorylation and enzymatic activity of DNMT1, and diminished global
DNA methylation. In mouse embryonic fibroblasts and primary mouse
astrocytes, FKBP51 mediated several effects of paroxetine, namely,
decreased the protein-protein interactions of DNMT1 with CDK5 and
FKBP52, reduced phosphorylation of DNMT1, and decreased the methylation
and increased the expression of the gene encoding brain-derived
neurotrophic factor (Bdnf). In human peripheral blood cells, FKBP5
expression inversely correlated with both global and BDNF methylation.
Peripheral blood cells isolated from depressed patients that were then
treated ex vivo with paroxetine revealed that the abundance of BDNF
positively correlated and phosphorylated DNMT1 inversely correlated with
that of FKBP51 in cells and with clinical treatment success in patients,
supporting the relevance of this FKBP51-directed pathway that prevents
epigenetic suppression of gene expression.
