| RRC ID |
19650
|
| 著者 |
Ohno S, Yukinawa F, Noda M, Nakajin S.
|
| タイトル |
Mono-(2-ethylhexyl) phthalate induces NR4A subfamily and GIOT-1 gene expression, and suppresses CYP19 expression in human granulosa-like tumor cell line KGN.
|
| ジャーナル |
Toxicol Lett
|
| Abstract |
The mechanism for transcriptional suppression of CYP19 by mono-ethylhexyl phthalate (MEHP) in a human ovarian granulosa cell line (KGN) was investigated. It is known that the CYP19 gene transcript in KGN cells predominantly includes exon PII among the 11 alternate exon I sequences. MEHP was found to significantly suppress Forskolin (FSK)-induced CYP19 gene transcription, CYP19 promoter II activity and CYP19 enzyme activity in a dose-dependent manner. Promoter assays using 5'-deleted promoter II reporter constructs suggested that the region important for responsiveness to MEHP exposure includes a putative CRE-like sequence and an SF-1 (NR5A1)/LRH-1 (NR5A2) binding sequence. Meanwhile, MEHP exposure rapidly and transiently induced nuclear receptor 4A (NR4A) mRNA, and gradually and continuously induced gonadotropin-inducible ovarian transcription factor-1 (GIOT-1; ZNF461) mRNA in KGN cells. The ectopic expression of NR4As and GIOT-1 suppressed promoter II activity, while among the NR4As expressed, only Nur77 (NR4A1) secondarily induced GIOT-1 mRNA expression. Based on these results, we believe that induction of the Nur77-GIOT-1 system by MEHP is involved in the transcriptional suppression of the CYP19 gene, and GIOT-1 may attenuate the promoter II activity due to suppression of SF-1 and/or LRH-1 transactivation in KGN cells.
|
| 巻・号 |
191(2-3)
|
| ページ |
353-9
|
| 公開日 |
2009-12-15
|
| DOI |
10.1016/j.toxlet.2009.10.004
|
| PII |
S0378-4274(09)01445-3
|
| PMID |
19822197
|
| MeSH |
Aromatase / biosynthesis*
Aromatase / genetics
Binding Sites
Cell Line, Tumor
Diethylhexyl Phthalate / analogs & derivatives*
Diethylhexyl Phthalate / toxicity
Female
Gene Expression / drug effects
Granulosa Cells / drug effects
Granulosa Cells / enzymology*
Humans
Luciferases / metabolism
Nuclear Receptor Subfamily 4, Group A, Member 1 / biosynthesis*
Nuclear Receptor Subfamily 4, Group A, Member 1 / genetics
Plasmids / genetics
Promoter Regions, Genetic / drug effects
RNA / biosynthesis
RNA / isolation & purification
Reverse Transcriptase Polymerase Chain Reaction
Transcription Factors / biosynthesis*
Transcription Factors / genetics
Transcriptional Activation / drug effects
Transfection
|
| IF |
3.569
|
| 引用数 |
12
|
|
WOS 分野
|
TOXICOLOGY
|
| リソース情報 |
| ヒト・動物細胞 |
KGN(RCB1154) |
