F-box/WD repeat-containing protein 7 is a protein that in humans is encoded by the FBXW7 gene. [5] [6] [7]
F-box/WD repeat-containing protein 7 is a protein that in humans is encoded by the FBXW7 gene. [5] [6] [7]
This gene encodes a member of the F-box protein 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 WD-40 domains, Fbls containing leucine-rich repeats, 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 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 [e.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 [8] and multiple myelomas require constitutive NF-κB signaling; therefore, disruption of FBXW7-mediated ubiquitylation of IκBd in these tumors results in cell death. [9] [10]
Three transcript variants encoding three different isoforms have been found for this gene. [7]
FBXW7 has been shown to interact with:
Ubiquitin is a small regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ubiquitously. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the 1970s and 1980s. Four genes in the human genome code for ubiquitin: UBB, UBC, UBA52 and RPS27A.
A 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 from the E2 to the protein substrate. The ubiquitin is attached to a lysine on the target protein by an isopeptide bond. E3 ligases interact with both the target protein and the E2 enzyme, and so impart substrate specificity to the E2. Commonly, E3s polyubiquitinate their substrate with Lys48-linked chains of ubiquitin, targeting the substrate for destruction by the proteasome. However, many other types of linkages are possible and alter a protein's activity, interactions, or localization. Ubiquitination by E3 ligases regulates diverse areas such as cell trafficking, DNA repair, and signaling and is of profound importance in cell biology. E3 ligases are also key players in cell cycle control, mediating the degradation of cyclins, as well as cyclin dependent kinase inhibitor proteins. The human genome encodes over 600 putative E3 ligases, allowing for tremendous diversity in substrates.
Skp, Cullin, F-box containing complex is a multi-protein E3 ubiquitin ligase complex that catalyzes the ubiquitination of proteins destined for 26S proteasomal degradation. Along with the anaphase-promoting complex, SCF has important roles in the ubiquitination of proteins involved in the cell cycle. The SCF complex also marks various other cellular proteins for destruction.
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.
S-phase kinase-associated protein 2 is an enzyme that in humans is encoded by the SKP2 gene.
E3 ubiquitin-protein ligase NEDD4, also known as neural precursor cell expressed developmentally down-regulated protein 4 is an enzyme that is, in humans, encoded by the NEDD4 gene.
The cell division cycle protein 20 homolog is an essential regulator of cell division that is encoded by the CDC20 gene in humans. To the best of current knowledge its most important function is to activate the anaphase promoting complex (APC/C), a large 11-13 subunit complex that initiates chromatid separation and entrance into anaphase. The APC/CCdc20 protein complex has two main downstream targets. Firstly, it targets securin for destruction, enabling the eventual destruction of cohesin and thus sister chromatid separation. It also targets S and M-phase (S/M) cyclins for destruction, which inactivates S/M cyclin-dependent kinases (Cdks) and allows the cell to exit from mitosis. A closely related protein, Cdc20homologue-1 (Cdh1) plays a complementary role in the cell cycle.
Cullin 1, also known as CUL1, is a human protein and gene from cullin family. This protein plays an important role in protein degradation and protein ubiquitination.
Cullin-4A is a protein that in humans is encoded by the CUL4A gene. CUL4A belongs to the cullin family of ubiquitin ligase proteins and is highly homologous to the CUL4B protein. CUL4A regulates numerous key processes such as DNA repair, chromatin remodeling, spermatogenesis, haematopoiesis and the mitotic cell cycle. As a result, CUL4A has been implicated in several cancers and the pathogenesis of certain viruses including HIV. A component of a CUL4A complex, Cereblon, was discovered to be a major target of the teratogenic agent thalidomide.
Cyclin-A2 is a protein that in humans is encoded by the CCNA2 gene. It is one of the two types of cyclin A: cyclin A1 is expressed during meiosis and embryogenesis while cyclin A2 is expressed in dividing somatic cells.
F-box/WD repeat-containing protein 1A (FBXW1A) also known as βTrCP1 or Fbxw1 or hsSlimb or pIkappaBalpha-E3 receptor subunit is a protein that in humans is encoded by the BTRC gene.
CDC34 is a gene encoding a protein product that has ubiquitin conjugating activity. CDC34 was originally discovered by work in baker's yeast as a gene that has a role in the cell division cycle. Cdc34 in yeast targets numerous substrates for ubiquitin mediated degradation. Ubiquitin-conjugating enzyme E2 R1 is a protein that in humans is encoded by the CDC34 gene.
Cyclin-dependent kinases regulatory subunit 1 is a protein that in humans is encoded by the CKS1B gene.
Ubiquitin-conjugating enzyme E2 C is a protein that in humans is encoded by the UBE2C gene.
βTrCP2 is a protein that in humans is encoded by the FBXW11 gene.
Mastermind-like protein 1 is a protein that in humans is encoded by the MAML1 gene.
F-box/WD repeat-containing protein 2 is a protein that in humans is encoded by the FBXW2 gene.
G2/mitotic-specific cyclin-F is a protein that in humans is encoded by the CCNF gene.
S-phase kinase-associated protein 1 is an enzyme that in humans is encoded by the SKP1 gene.
Cdc4 is a substrate recognition component of the SCF ubiquitin ligase complex, which acts as a mediator of ubiquitin transfer to target proteins, leading to their subsequent degradation via the ubiquitin-proteasome pathway. Cdc4 targets primarily cell cycle regulators for proteolysis. It serves the function of an adaptor that brings target molecules to the core SCF complex. Cdc4 was originally identified in the model organism Saccharomyces cerevisiae. CDC4 gene function is required at G1/S and G2/M transitions during mitosis and at various stages during meiosis.
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