Home > A. Molecular pathology > FBXW7

FBXW7

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.

Pathology

- 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.

By tumors

- Wilms tumor (#20332316#)

  • 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.

- MYCN is a target of FBXW7-mediated ubiquitination and degradation. It suggests that a common pathway is dysregulated by different mechanisms in various WT subtypes. (#20332316#)

See also

- WIlms tumor (nephroblastoma)

References

- 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#

- Welcker M, Clurman BE. FBW7 ubiquitin ligase: a tumour suppressor at the crossroads of cell division, growth and differentiation. Nat Rev Cancer. 2007 Dec 20; PMID: #18094723#

- 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#