title: Metal transcription factor-1 is involved in hypoxia-dependent regulation of placenta growth factor in trophoblast-derived cells.
abstract: Placenta growth factor (PlGF) is a placental angiogenic factor. Metal-responsive transcription factor (MTF)-1 was reported to take part in the hypoxic induction of PlGF in RAS-transformed mouse fibroblasts. We contrarily showed that PlGF mRNA and protein levels decreased under hypoxia in a choriocarcinoma BeWo cell line derived from trophoblast. In this report, we examined whether hypoxia-dependent regulation of the PlGF gene in these cells also depends on MTF-1. We analyzed the effect of hypoxia on MTF-1 expression, and it was revealed to be decreased. Moreover, MTF-1 small interfering RNA treatment decreased PlGF mRNA level. To investigate the transcription of PlGF under hypoxia, we cloned promoter region of the human PlGF. Promoter deletion analysis suggested that triple repeats of metal-responsive element located between -511 and -468 bp in the promoter are important for the hypoxic regulation of PlGF. Treatment with MTF-1 small interfering RNA resulted in the significant decreased luciferase activity in PlGF reporter constructs. Chromatin immunoprecipitation showed the binding of the MTF-1 protein to the promoter region. We examined MTF-1 immunoreactivity in trophoblasts of term placental tissue from patients with normal pregnancies and preeclampsia, which represents a condition of placental hypoxia. Immunoreactivity of the MTF-1 protein was decreased in placentas from pregnant women with preeclampsia when compared with those from normal pregnant women. Taken together, these findings suggest that MTF-1 is involved in hypoxia-dependent regulation of PlGF in trophoblast-derived cells.
authors.affiliation: Department of Obstetrics and Gynecology, Osaka University Faculty of Medicine, Suita City, Osaka, Japan.
authors.forename: Fumihito
authors.initials: F
authors.lastname: Nishimoto
authors.forename: Masahiro
authors.initials: M
authors.lastname: Sakata
authors.forename: Ryoko
authors.initials: R
authors.lastname: Minekawa
authors.forename: Yoko
authors.initials: Y
authors.lastname: Okamoto
authors.forename: Asako
authors.initials: A
authors.lastname: Miyake
authors.forename: Aki
authors.initials: A
authors.lastname: Isobe
authors.forename: Toshiya
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Takashi
authors.initials: T
authors.lastname: Takeda
authors.forename: Emi
authors.initials: E
authors.lastname: Ishida
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Sawada
authors.forename: Ken-Ichiro
authors.initials: K
authors.lastname: Morishige
authors.forename: Tadashi
authors.initials: T
authors.lastname: Kimura
mesh_terms: D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000502:physiology; D015151:Immunoblotting; D007150:Immunohistochemistry; D000072483:Placenta Growth Factor; D016133:Polymerase Chain Reaction; D011225:Pre-Eclampsia / Q000378:metabolism / Q000473:pathology; D011247:Pregnancy; D011257:Pregnancy Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D014327:Trophoblasts / Q000166:cytology*; D000097809:Transcription Factor MTF-1
chemical_list: D004268:DNA-Binding Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins; D034741:RNA, Small Interfering; D014157:Transcription Factors; D000097809:Transcription Factor MTF-1; C497442:HIF1A protein, human; C000608036:PGF protein, human; C000608037:Pgf protein, mouse