MIM.606278 Chr. 4
Thursday 31 January 2008
Definition: FBW7 is a E3 ubiquitin ligase component.
Archipelago is an F-box protein with 7 tandem WD (tryptophan-aspartic acid) repeats. It binds directly to cyclin E1 (CCNE1) and is thought to target it for ubiquitin-mediated degradation.
FBW7 (F-box and WD repeat domain-containing 7) is the substrate recognition component of an evolutionary conserved SCF (complex of SKP1, CUL1 and F-box protein)-type ubiquitin ligase.
FBW7 (F-box and WD repeat domain-containing 7) has been characterized as an onco-suppressor protein in human cancers.
Recent studies have also shown that FBW7 exerts its anti-tumor function primarily by promoting the degradation of various oncoproteins, through which FBW7 regulates cellular proliferation, differentiation and causes genetic instability.
Fbw7-knockout mouse models support Fbw7 as a tumor suppressor gene in the development and progression of human malignancies.
FBW7 is also a tumour suppressor, the regulatory network of which is perturbed in many human malignancies.
Numerous cancer-associated mutations in FBW7 and its substrates have been identified, and loss of FBW7 function causes chromosomal instability and tumorigenesis.
- FBXW7 is a Wilms’ tumor gene and is mutated or deleted in approximately 4% of tumors examined.
- 21% of tumors with epithelial type histology after neoadjuvant chemotherapy had FBXW7 aberrations.
- WT patient can have germline mutations in both FBXW7 and WT1.
- Wilms tumor (WT), the most common pediatric renal malignancy, is associated with mutations in several well-characterized genes, most notably WT1, CTNNB1, WTX, and TP53.
WIlms tumor (nephroblastoma)
Tumor suppressor functions of FBW7 in cancer development and progression. Wang Z, Inuzuka H, Zhong J, Wan L, Fukushima H, Sarkar FH, Wei W. FEBS Lett. 2012 May 21;586(10):1409-18. doi : 10.1016/j.febslet.2012.03.017 PMID: 22673505
Subtype-specific FBXW7 mutation and MYCN copy number gain in Wilms’ tumor. Williams RD, Al-Saadi R, Chagtai T, Popov S, Messahel B, Sebire N, Gessler M, Wegert J, Graf N, Leuschner I, Hubank M, Jones C, Vujanic G, Pritchard-Jones K; Children’s Cancer and Leukaemia Group; SIOP Wilms’ Tumour Biology Group. Clin Cancer Res. 2010 Apr 1;16(7):2036-45. PMID: 20332316
Rajagopalan H, Lengauer C. hCDC4 and genetic instability in cancer. Cell Cycle. 2004 Jun;3(6):693-4. PMID: 15118416
Rajagopalan H, Jallepalli PV, Rago C, Velculescu VE, Kinzler KW, Vogelstein B, Lengauer C. Inactivation of hCDC4 can cause chromosomal instability. Nature. 2004 Mar 4;428(6978):77-81. PMID: 14999283