title: GCNF-dependent activation of cyclin D1 expression via repression of Mir302a during ESC differentiation.
abstract: Cyclin D1 plays an important role in the regulation of cellular proliferation and its expression is activated during gastrulation in the mouse; however, it remains unknown how cyclin D1 expression is regulated during early embryonic development. Here, we define the role of germ cell nuclear factor (GCNF) in the activation of cyclin D1 expression during embryonic stem cell (ESC) differentiation as a model of early development. During our study of GCNF knockout (GCNF(-) (/) (-) ) ESC, we discovered that loss of GCNF leads to the repression of cyclin D1 activation during ESC differentiation. This was determined to be an indirect effect of deregulation Mir302a, which is a cyclin D1 suppressor via binding to the 3'UTR of cyclin D1 mRNA. Moreover, we showed that Mir302 is a target gene of GCNF that inhibits Mir302 expression by binding to a DR0 element within its promoter. Inhibition of Mir302a using Mir302 inhibitor during differentiation of GCNF(-) (/) (-) ESCs restored cyclin D1 expression. Similarly over-expression of GCNF during differentiation of GCNF(-) (/) (-) ESCs rescued the inhibition of Mir302a expression and the activation of cyclin D1. These results reveal that GCNF plays a key role in regulating activation of cyclin D1 expression via inhibition of Mir302a.
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, USA; Department of Surgery, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, USA.
authors.forename: Hongran
authors.initials: H
authors.lastname: Wang
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Wang
authors.forename: Trevor K
authors.initials: TK
authors.lastname: Archer
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Zwaka
authors.forename: Austin J
authors.initials: AJ
authors.lastname: Cooney
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D049109:Cell Proliferation; D048430:Cell Shape; D003114:Colony-Forming Units Assay; D019938:Cyclin D1 / Q000235:genetics* / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D057136:Nuclear Receptor Subfamily 6, Group A, Member 1 / Q000172:deficiency / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000235:genetics; D012097:Repressor Proteins / Q000378:metabolism*
chemical_list: C558265:MIRN302 microRNA, mouse; D035683:MicroRNAs; D057136:Nuclear Receptor Subfamily 6, Group A, Member 1; D012097:Repressor Proteins; D019938:Cyclin D1
keywords: Cyclin D1; ESCs; GCNF; Mir302; microRNA