F-box/WD repeat-containing protein 7 is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
that in humans is encoded by the ''FBXW7''
gene
In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
.
Function
This gene encodes a member 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 which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of
ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into 3 classes: Fbws containing
WD40 domains, Fbls containing
leucine-rich repeat
A leucine-rich repeat (LRR) is a protein structural motif that forms an α/β horseshoe tertiary structure, fold. It is composed of repeating 20–30 amino acid stretches that are unusually rich in the hydrophobic amino acid leucine. These Pr ...
s, and Fbxs containing either different
protein-protein interaction modules or no recognizable motifs. The protein encoded by this gene was previously referred to as FBX30, and belongs to the Fbws class; in addition to an F-box, this protein contains 7 tandem WD40 repeats. This protein binds directly to
cyclin E
Cyclin E is a member of the cyclin family.
Cyclin E binds to G1 phase Cdk2, which is required for the transition from G1 to S phase of the cell cycle that determines initiation of DNA duplication. The Cyclin E/CDK2 complex phosphorylates p27 ...
and probably targets cyclin E for ubiquitin-mediated degradation. Other well established pro-proliferative targets of FBXW7 are c-Myc and Notch1. Mono-allelic mutations in this gene are detected in sporadic cancers
.g., cholangiocarcinoma (35%), T-ALL (31%), endometrial carcinoma (16%), colorectal carcinoma (16%), bladder cancer (10%), gastric carcinoma (6%), lung squamous cell carcinoma (5%), etc. These findings implicate the gene's potential role in the pathogenesis of human cancers. Despite being commonly acknowledged as a haploinsufficient tumor suppressor, mutations are not found in some cancers, such as acute myeloid leukemia and multiple myeloma. One possibility is that FBXW7 substrate stabilization is detrimental in these neoplasms. For example, the FBXW7 substrate C/EBPα suppresses AML
and multiple myelomas require constitutive
NF-κB
Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a family of transcription factor protein complexes that controls transcription (genetics), transcription of DNA, cytokine production and cell survival. NF-κB is found i ...
signaling; therefore, disruption of FBXW7-mediated ubiquitylation of IκBd in these tumors results in cell death.
Three transcript variants encoding three different isoforms have been found for this gene.
Interactions
FBXW7 has been shown to
interact with:
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MYB,
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PPARGC1A,
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Parkin (ligase)
Parkin is a 465-amino acid residue E3 ubiquitin ligase, a protein that in humans and mice is encoded by the ''PARK2'' gene. Parkin plays a critical role in ubiquitination – the process whereby molecules are covalently labelled with ubiquitin ...
,
and
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SKP1A
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-bo ...
.
References
Further reading
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{{PDB Gallery, geneid=55294