A novel transcriptional element which regulates expression of the CYP2D4 gene by Oct-1 and YY-1 binding.
We first identified the transcriptional regulatory element of the CYP2D4 gene. CYP2D4 is of interest in brain pharmacology and physiology because this enzyme can be involved in the metabolism of endogenous and exogenous compounds, which act on the central nervous system. Transfection studies using a series of the CYP2D4 promoter luciferase constructs identified the transcriptional element of CYP2D4 in the sequence between nucleotides -116 and -90 (named the neural expression regulatory element, NERE). The nucleotide sequence of NERE was specific for the CYP2D4 gene. Within this region, two nuclear factor-binding sequences, Oct-1 and YY-1, were present. Oct-1 acts as the activator of the CYP2D4. The core sequence of the YY-1 binding motif partially overlapped that of the Oct-1 binding motif. YY-1 may act as the repressor of CYP2D4, which interferes with Oct-1 activation by its binding to NERE. We concluded that a novel transcriptional regulatory element NERE specifically regulates the expression of the CYP2D4. This regulation system may be involved in the unique distribution of this isoform, such as the expression in the brain.
Mizuno
Dai
D
Department of Chemical Biology, Osaka City University Medical School, 1-4-3, Asahimachi, Abeno-ku, Osaka 545-8585, Japan.
Takahashi
Yoshiki
Y
Hiroi
Toyoko
T
Imaoka
Susumu
S
Kamataki
Tetsuya
T
Funae
Yoshihiko
Y
D000595:Amino Acid Sequence; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism*; D001665:Binding Sites; D002454:Cell Differentiation / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D050981:Erythroid-Specific DNA-Binding Factors; D005786:Gene Expression Regulation; D051863:Host Cell Factor C1; D006899:Mixed Function Oxygenases / Q000235:genetics* / Q000378:metabolism*; D008969:Molecular Sequence Data; D009474:Neurons / Q000166:cytology / Q000502:physiology; D050811:Octamer Transcription Factor-1; D016716:PC12 Cells; D051381:Rats; D012045:Regulatory Sequences, Nucleic Acid; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation
D004268:DNA-Binding Proteins; D050981:Erythroid-Specific DNA-Binding Factors; D051863:Host Cell Factor C1; D050811:Octamer Transcription Factor-1; C494168:Pou2f1 protein, rat; D014157:Transcription Factors; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C115670:Cyp2d4 protein, rat