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1. Mol Pharmacol. 2012 Feb 21. [Epub ahead of print]

Time-dependent Interaction Between DEC2 and C/EBPα Underlies the Circadian
Expression of CYP2D6 in Serum-shocked HepG2 Cells.

Matsunaga N, Inoue M, Kusunose N, Kakimoto K, Hamamura K, Hanada Y, Toi A,
Yoshimura Y, Sato F, Fujimoto K, Koyanagi S, Ohdo S.

1 Kyushu University;

Differentiated embryo chondrocyte-2 (DEC2), also known as bHLHE41 or Sharp1, is a
pleiotropic transcription repressor that controls the expression of genes
involved in cellular differentiation, hypoxia responses, apoptosis, and circadian
rhythm regulation. Although a previous study demonstrated that DEC2 participates
in the circadian control of hepatic metabolism by regulating the expression of
cytochrome P450 (CYPs), the molecular mechanism is not fully understood. We
demonstrated previously that brief exposure of HepG2 cells to 50% serum resulted
in 24-h oscillation in the expression of CYP3A4 as well as circadian clock genes.
In this study, we found that the expression of CYP2D6, a major drug-metabolizing
enzyme in humans, also exhibited a significant oscillation in serum-shocked HepG2
cells. DEC2 interacted with C/EBPα accompanied by forming a complex with histone
deacetylase-1, which suppressed the transcriptional activity of C/EBPα to induce
the expression of CYP2D6. The oscillation in the protein levels of DEC2 in
serum-shocked HepG2 cells was nearly anti-phase to that in the mRNA levels of
CYP2D6. Transfection of cells with siRNA against DEC2 decreased the amplitude of
CYP2D6 mRNA oscillation in serum-shocked cells. These results suggest that DEC2
periodically represses the promoter activity of CYP2D6, resulting in its
circadian expression in serum-shocked cells. DEC2 appears to constitute a
molecular link through which output components from the circadian clock are
associated with the time-dependent expression of hepatic drug-metabolizing
enzyme.

PMID: 22355045 [PubMed - as supplied by publisher]