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PMID:12665572

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Citation

Tokuzawa, Y, Kaiho, E, Maruyama, M, Takahashi, K, Mitsui, K, Maeda, M, Niwa, H and Yamanaka, S (2003) Fbx15 is a novel target of Oct3/4 but is dispensable for embryonic stem cell self-renewal and mouse development. Mol. Cell. Biol. 23:2699-708

Abstract

Embryonic stem (ES) cells are immortal and pluripotent cells derived from early mammalian embryos. Transcription factor Oct3/4 is essential for self-renewal of ES cells and early mouse development. However, only a few Oct3/4 target genes have been identified. In this study, we found that F-box-containing protein Fbx15 was expressed predominantly in mouse undifferentiated ES cells. Inactivation of Oct3/4 in ES cells led to rapid extinction of Fbx15 expression. Reporter gene analyses demonstrated that this ES cell-specific expression required an 18-bp enhancer element located approximately 500 nucleotides upstream from the transcription initiation site. The enhancer contained an octamer-like motif and an adjacent Sox-binding motif. Deletion or point mutation of either motif abolished the enhancer activity. The 18-bp fragment became active in NIH 3T3 cells when Oct3/4 and Sox2 were coexpressed. A gel mobility shift assay demonstrated cooperative binding of Oct3/4 and Sox2 to the enhancer sequence. In mice having a beta-galactosidase gene knocked into the Fbx15 locus, 5-bromo-4-chloro-3-indolyl-beta-D-galactopyranoside staining was detected in ES cells, early embryos (two-cell to blastocyst stages), and testis tissue. Despite such specific expression of Fbx15, homozygous mutant mice showed no gross developmental defects and were fertile. Fbx15-null ES cells were normal in morphology, proliferation, and differentiation. These data demonstrate that Fbx15 is a novel target of Oct3/4 but is dispensable for ES cell self-renewal, development, and fertility.

Links

PubMed PMC152544

Keywords

3T3 Cells; Animals; Cell Division; Cell Line; DNA-Binding Proteins/deficiency; DNA-Binding Proteins/genetics; DNA-Binding Proteins/metabolism; Embryonic and Fetal Development/genetics; Embryonic and Fetal Development/physiology; Enhancer Elements, Genetic; F-Box Proteins; Gene Expression Regulation, Developmental; Gene Targeting; Ligases/genetics; Ligases/metabolism; Male; Mice; Mice, Knockout; Mutagenesis, Site-Directed; Octamer Transcription Factor-3; Pluripotent Stem Cells/cytology; Pluripotent Stem Cells/metabolism; Transcription Factors/deficiency; Transcription Factors/genetics; Transcription Factors/metabolism; Ubiquitin/metabolism

Significance

Annotations

Gene product Qualifier GO ID GO term name Evidence Code with/from Aspect Notes Status


See also

References

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