title: Transcriptional cooperation between p53 and NF-κB p65 regulates microRNA-224 transcription in mouse ovarian granulosa cells.
abstract: MicroRNAs (miRNAs) have been indicated to play key roles in ovarian follicular development. However, little is known about how the miRNA gene expression itself is regulated in the mammalian ovary. We previously reported that miR-224 is involved in TGF-β1-mediated follicular granulosa cell (GC) growth and estradiol (E2) production by targeting Smad4. Here, the transcriptional regulation of miR-224 expression in GCs was further investigated. Our results showed that both the tumor suppressor gene p53 and NF-κB p65 subunit suppressed the TGF-β1-induced increase in pri-miR-224 expression in GCs. ChIP assays demonstrated that TGF-β1 enhanced the binding of p53 and p65 to the proximal promoter region of GABAA receptor ε subunit (miR-224 host gene). p53 and p65 transcriptionally cooperated to inactivate the GABAA receptor ε subunit promoter. In addition, p53/p65 could up-regulate Smad4 expression by inhibiting its target miR-224 in GCs which contributed, at least partially, to the effects of miR-224 and Smad4 on GC proliferation and E2 release. Our results provide new data about the interplay between transcription factors involved in GC proliferation and function by cooperatively regulating miRNA expression.
authors.affiliation: Department of Cell and Developmental Biology, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, People's Republic of China.
authors.forename: Meng
authors.initials: M
authors.lastname: Liang
authors.forename: Guidong
authors.initials: G
authors.lastname: Yao
authors.forename: Mianmian
authors.initials: M
authors.lastname: Yin
authors.forename: Mingrong
authors.initials: M
authors.lastname: Lü
authors.forename: Hui
authors.initials: H
authors.lastname: Tian
authors.forename: Lin
authors.initials: L
authors.lastname: Liu
authors.forename: Jie
authors.initials: J
authors.lastname: Lian
authors.forename: Xingxu
authors.initials: X
authors.lastname: Huang
authors.forename: Fei
authors.initials: F
authors.lastname: Sun
mesh_terms: D016475:3T3 Cells; D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D005260:Female; D006107:Granulosa Cells / Q000378:metabolism*; D051379:Mice; D008813:Mice, Inbred ICR; D035683:MicroRNAs / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D034622:RNA Interference; D034741:RNA, Small Interfering; D011963:Receptors, GABA-A / Q000235:genetics; D051901:Smad4 Protein / Q000096:biosynthesis; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: C546277:Gabre protein, mouse; C584584:MIRN224 microRNA, mouse; D035683:MicroRNAs; D034741:RNA, Small Interfering; D011963:Receptors, GABA-A; C498144:Rela protein, mouse; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; D051996:Transcription Factor RelA; D053773:Transforming Growth Factor beta1; D016159:Tumor Suppressor Protein p53