|CSC-DC005627||Panoply™ Human FBXW7 Knockdown Stable Cell Line||Inquiry|
|CSC-RT0018||Human FBXW7 Knockout Cell Line-DLD-1||Inquiry|
|CSC-RT0029||Human FBXW7 Knockout Cell Line-DLD-1||Inquiry|
|CSC-RT0071||Human FBXW7 Knockout Cell Line-HCT116||Inquiry|
|CSC-RT0661||Human FBXW7 Knockout Cell Line-HEK293T||Inquiry|
|CSC-SC005627||Panoply™ Human FBXW7 Over-expressing Stable Cell Line||Inquiry|
|CDCB159989||Human FBXW7 ORF clone (NM_033632.2)||Inquiry|
|CDCB184193||Rabbit FBXW7 ORF clone (XM_008267332.1)||Inquiry|
|CDCL107519||Human FBXW7 ORF clone (NM_001013415.1)||Inquiry|
|CDCL107521||Human FBXW7 ORF clone (NM_018315.4)||Inquiry|
|CDCL107523||Human FBXW7 ORF clone (NM_001257069.1)||Inquiry|
|CDCL107527||Human Fbxw7 ORF clone (NM_001177773.1)||Inquiry|
|CDCR242745||Mouse Fbxw7 ORF Clone(NM_001177774.1)||Inquiry|
|CDCR264792||Mouse Fbxw7 ORF Clone(NM_080428.3)||Inquiry|
|CDCS406529||Human FBXW7 ORF Clone (BC117244)||Inquiry|
|CDFG021497||Mouse Fbxw7 cDNA Clone(NM_001177773.1)||Inquiry|
|CDFG021502||Mouse Fbxw7 cDNA Clone(NM_001177774.1)||Inquiry|
|CDFH006713||Human FBXW7 cDNA Clone(NM_001013415.1)||Inquiry|
|MiUTR1H-03577||FBXW7 miRNA 3'UTR clone||Inquiry|
|MiUTR1H-03578||FBXW7 miRNA 3'UTR clone||Inquiry|
|MiUTR3H-08333||FBXW7 miRNA 3'UTR clone||Inquiry|
FBXW7 (also known as CDC4, FBW6, FBW7, hAgo, Sel10, hCdc4, etc.) is an evolutionary conserved gene which encodes protein that belongs to the F-box family that consisted of estimated 70 proteins in humans. The FBXW7 gene family was initially found to regulate the location of CDK (cyclin recombinase) inhibitor Sic1 in budding yeast and was named Cdc4. Further investigation identified FBXW7 on the human chromosomal region 4q31.3 (200 kDa) for the identification of the human orthologue. FBXW7 gene encodes for three protein isoforms: FBXW7α (the most extensively studied isoform among these three, localizes in the nucleus and is found ubiquitously in tissue), FBXW7β (localizes in the ER/cytoplasm and is found predominantly in brain), FBXW7γ (localizes in the nucleolus and is found in heart and skeletal muscle), each isoform has dimerization domain, sharing ten common exons and differ only at their N-termini by a single isoform-specific first exon. The F-box domain recruits other components of the ubiquitin ligase complex, and WD40 repeatedly binds to the substrate.
FBXW7, a substrate recognition subunit of the E3 ubiquitin ligase molecule and a part of the SCF/β-TrCP (Skp1-Cdc53/Cullin-F-box-protein) complex, has influence on many pathways and plays pivotal roles in cell division, growth, and is responsible for substrate recognition, which targets multiple transcriptional activators and oncoproteins including Cyclin E, Notch1, Notch4, c-JUN, and c-MYC. FBXW7 binds each of the substrates above through a conserved phosphorylated domain - namely, the Cdc4 phosphodegron. Due to most of these proteins targeted by Fbxw7 for degradation are proto-oncoproteins, Fbxw7 has been conferring the function of a tumor suppressor.
Figure 1. The role of Fbxw7 in protein degradation (Takeishi et al. 2014)
FBXW7 is a haploin-sufficient gene that promotes non-homologous end-joining (NHEJ) repair, and FBXW7 depletion causes radio-sensitization. In response to ionizing radiation, ATM phosphorylates FBXW7 at serine 26 to recruit it to DSB (Double Strand Breaks) sites, such activated DNA-PKcs phosphorylates XRCC4 at serines 325/326, thereby promotes the binding of XRCC4 to FBXW7. And SCFFBXW7 E3 ligase subsequently promotes polyubiquitination of XRCC4 at lysine 296 through lysine 63 linkage to enhance binding to the Ku70/80 complex, as a result, to promoting NHEJ repair. The process demonstrates one mechanism that FBXW7 guarantees genome integrity.
Figure 2. One Mechanism that FBXW7 Contributes to Genome Integrity (Zhang et al. 2016)
The human FBXW7 protein essentially denotes an F-box protein with 8-WD repeats. These key domains enable FBXW7 to perform its function through protein-protein interaction. The F-box domain recruits the SCF complex through direct contact with the adaptor SKP1. The WD40 domain has a binding pocket for phosphorylation degradation that interacts with the phosphorylated substrate. By this procession, FBXW7 bridges the interaction between the substrate and the core SCF, mediating the transfer of ubiquitin from E2 to the target protein for degradation.
FBXW7 Mutation Associated Diseases
Evidences indicated that FBXW7 works as a putative tumor suppressor in human tumorigenesis, meanwhile, FBXW7 inactivation or loss of FBXW7 will subsequently result in genomic instability, and may finally lead to oncogenesis. Heterozygous mutations in FBXW7 have been detected in several types of human cancers. In fact, FBXW7 mutations are found in 6% of tumors making it the 4th most frequently mutated gene, the frequencies are even higher in individual malignancies including cholangiomas (35%), T-cell acute lymphocytic leukemia (31%), colorectal cancer (10%), etc. Most of these mutations are point mutations, which lead to key positions amino-acid substitutions in the WD40 repeats, accordingly, result in the disruption of substrate binding. However, rest of the mutations are mostly nonsense mutations that leads to non-functional Fbxw7. These clinical observations indicate that fbxw7 plays an important role in cell cycle regulation and is as well important for preventing tumorigenesis.
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