F-box protein 15 also known as Fbx15 is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...

that in humans is encoded by the FBXO15

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...

Function

Members of the

F-box protein F-box proteins are proteins containing at least one F-box domain. The first identified F-box protein is one of three components of the SCF complex, which mediates ubiquitination of proteins targeted for degradation by the 26S proteasome. Core co ...

family, such as FBXO15, are characterized by an approximately 40-amino acid F-box motif. SCF complexes, formed by

SKP1 S-phase kinase-associated protein 1 is an enzyme that in humans is encoded by the ''SKP1'' gene. This gene encodes a protein that is a member of the SCF ubiquitin ligase protein complex. It binds to F-box proteins (proteins containing an F-box ...

cullin Cullins are a family of hydrophobic scaffold proteins which provide support for ubiquitin ligases (E3). All eukaryotes appear to have cullins. They combine with RING proteins to form ''Cullin-RING ubiquitin ligases'' (CRLs) that are highly dive ...

, and F-box proteins, act as protein-

ubiquitin ligase A ubiquitin ligase (also called an E3 ubiquitin ligase) is a protein that recruits an E2 ubiquitin-conjugating enzyme that has been loaded with ubiquitin, recognizes a protein substrate, and assists or directly catalyzes the transfer of ubiquitin ...

s. F-box proteins interact with SKP1 through the F box, and they interact with ubiquitination targets through other protein interaction domains. Biochemically, Fbx15 is a substrate receptor of an ubiquitin ligase belonging to the family of the F-box proteins. Differently from other F-box proteins, Fbx15 recognizes its substrate Kif1-Binding Protein (KBP) in an acetylation dependent manner.

Importance in embryonic stem cells

Fbxo15 is a protein expressed in un differentiated

embryonic stem cell Embryonic stem cells (ESCs) are pluripotent stem cells derived from the inner cell mass of a blastocyst, an early-stage pre- implantation embryo. Human embryos reach the blastocyst stage 4–5 days post fertilization, at which time they consi ...

s. It is expressed during coexpression of

Oct3/4 Oct-4 (octamer-binding transcription factor 4), also known as POU5F1 (POU domain, class 5, transcription factor 1), is a protein that in humans is encoded by the ''POU5F1'' gene. Oct-4 is a homeodomain transcription factor of the POU family. I ...

c-Myc ''Myc'' is a family of regulator genes and proto-oncogenes that code for transcription factors. The ''Myc'' family consists of three related human genes: ''c-myc'' (MYC), ''l-myc'' (MYCL), and ''n-myc'' (MYCN). ''c-myc'' (also sometimes referre ...

, Klf4, and SOX2, four genes identified to be important in embryonic stem cell self-renewal and differentiation repression. In mice having a beta-galactosidase gene knocked into the Fbx15 locus, stain was detected in ES cells, early embryos (from two-cell to blastocyst stages), and testis tissue. There is an enhancer site upstream of the Fbx15-encoding transcription gene that contains an octamer-like binding motif and a Sox-like binding motif. Reporter gene analyses demonstrated that the ES cell-specific expression required this 18-bp enhancer element located approximately 500 nucleotides upstream from the transcription initiation site. Deletion or point mutation of either motif abolished the enhancer activity. It became active in NIH 3T3 cells when Oct3/4 and Sox2 were coexpressed and cooperatively bind to the enhancer sequence. Targeted deletion of the ''Fbx15'' gene in mice does not result in embryonic lethality or gross developmental aberrations, despite the fact that ''Fbx15^-/-'' mice are sub-fertile when compared to their wild-type counterparts. This might be explained by the fact that ''Fbx15^-/-'' embryonic stem cells display a proliferation defect - caused by the accumulation of the Fbx15 substrate KBP - generating a short-term bottleneck during the early stages of embryogenesis. In fact, targeting of KBP is required to prevent an unscheduled mitochondrial biogenesis that, in naïve pluripotent stem cells, causes increased mitochondrial oxidative phosphorylation and production of reactive oxygen species. The selective expression of Fbx15 and its dependency on the activity of the pluripotency core factors Oct3/4 and Sox2 promoted the use of the expression of Fbx15 as the first marker of reprogramming of fibroblasts into induced pluripotent stem cells.

References

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