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[4] and multiple myelomas require constitutive NF-κB signaling; therefore, disruption of FBXW7-mediated ubiquitylation of IκBd in these tumors results in cell death.[5][6]
Three transcript variants encoding three different isoforms have been found for this gene.[3]
↑Gupta-Rossi N, Le Bail O, Gonen H, Brou C, Logeat F, Six E, Ciechanover A, Israël A (Sep 2001). "Functional interaction between SEL-10, an F-box protein, and the nuclear form of activated Notch1 receptor". J Biol Chem. 276 (37): 34371–8. doi:10.1074/jbc.M101343200. PMID11425854.
↑ 9.09.1Staropoli JF, McDermott C, Martinat C, Schulman B, Demireva E, Abeliovich A (Mar 2003). "Parkin is a component of an SCF-like ubiquitin ligase complex and protects postmitotic neurons from kainate excitotoxicity". Neuron. 37 (5): 735–49. doi:10.1016/s0896-6273(03)00084-9. PMID12628165.
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Maruyama K, Sugano S (1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID8125298.
Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID9373149.
Oberg C, Li J, Pauley A, Wolf E, Gurney M, Lendahl U (2001). "The Notch intracellular domain is ubiquitinated and negatively regulated by the mammalian Sel-10 homolog". J. Biol. Chem. 276 (38): 35847–53. doi:10.1074/jbc.M103992200. PMID11461910.
Koepp DM, Schaefer LK, Ye X, Keyomarsi K, Chu C, Harper JW, Elledge SJ (2001). "Phosphorylation-dependent ubiquitination of cyclin E by the SCFFbw7 ubiquitin ligase". Science. 294 (5540): 173–7. doi:10.1126/science.1065203. PMID11533444.
Moberg KH, Bell DW, Wahrer DC, Haber DA, Hariharan IK (2001). "Archipelago regulates Cyclin E levels in Drosophila and is mutated in human cancer cell lines". Nature. 413 (6853): 311–6. doi:10.1038/35095068. PMID11565033.
Strohmaier H, Spruck CH, Kaiser P, Won KA, Sangfelt O, Reed SI (2001). "Human F-box protein hCdc4 targets cyclin E for proteolysis and is mutated in a breast cancer cell line". Nature. 413 (6853): 316–22. doi:10.1038/35095076. PMID11565034.
Spruck CH, Strohmaier H, Sangfelt O, Müller HM, Hubalek M, Müller-Holzner E, Marth C, Widschwendter M, Reed SI (2002). "hCDC4 gene mutations in endometrial cancer". Cancer Res. 62 (16): 4535–9. PMID12183400.
Li J, Pauley AM, Myers RL, Shuang R, Brashler JR, Yan R, Buhl AE, Ruble C, Gurney ME (2002). "SEL-10 interacts with presenilin 1, facilitates its ubiquitination, and alters A-beta peptide production". J. Neurochem. 82 (6): 1540–8. doi:10.1046/j.1471-4159.2002.01105.x. PMID12354302.
Staropoli JF, McDermott C, Martinat C, Schulman B, Demireva E, Abeliovich A (2003). "Parkin is a component of an SCF-like ubiquitin ligase complex and protects postmitotic neurons from kainate excitotoxicity". Neuron. 37 (5): 735–49. doi:10.1016/S0896-6273(03)00084-9. PMID12628165.
Welcker M, Singer J, Loeb KR, Grim J, Bloecher A, Gurien-West M, Clurman BE, Roberts JM (2003). "Multisite phosphorylation by Cdk2 and GSK3 controls cyclin E degradation". Mol. Cell. 12 (2): 381–92. doi:10.1016/S1097-2765(03)00287-9. PMID14536078.
Busino L, Donzelli M, Chiesa M, Guardavaccaro D, Ganoth D, Dorrello NV, Hershko A, Pagano M, Draetta GF (2003). "Degradation of Cdc25A by beta-TrCP during S phase and in response to DNA damage". Nature. 426 (6962): 87–91. doi:10.1038/nature02082. PMID14603323.
Cassia R, Moreno-Bueno G, Rodríguez-Perales S, Hardisson D, Cigudosa JC, Palacios J (2004). "Cyclin E gene (CCNE) amplification and hCDC4 mutations in endometrial carcinoma". J. Pathol. 201 (4): 589–95. doi:10.1002/path.1474. PMID14648662.
Nateri AS, Riera-Sans L, Da Costa C, Behrens A (2004). "The ubiquitin ligase SCFFbw7 antagonizes apoptotic JNK signaling". Science. 303 (5662): 1374–8. doi:10.1126/science.1092880. PMID14739463.
