FBXW7/hCDC4 is a general tumor suppressor in human cancer
2007 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 67, no 19, 9006-9012 p.Article in journal (Refereed) Published
The ubiquitin-proteasome system is a major regulatory pathway of protein degradation and plays an important role in cellular division. Fbxw7 (or hCdc4), a member of the F-box family of proteins, which are substrate recognition components of the multisubunit ubiquitin ligase SCF (Skpl-Cdc53/ Cullin-F-box-protein), has been shown to mediate the ubiquitin-dependent proteolysis of several oncoproteins including cyclin El, c-Myc, c-Jun, and Notch. The oncogenic potential of Fbxw7 substrates, frequent allelic loss in human cancers, and demonstration that mutation of FBXW7 cooperates with p53 in mouse tumorigenesis have suggested that Fbxw7 could function as a tumor suppressor in human cancer. Here, we carry out an extensive genetic screen of primary tumors to evaluate the role of FBXW7 as a tumor suppressor in human tumorigenesis. Our results indicate that FBXW7 is inactivated by mutation in diverse human cancer types with an overall mutation frequency of ∼ 6%. The highest mutation frequencies were found in tumors of the bile duct (cholangio-carcinomas, 35%), blood (T-cell acute lymphocytic leukemia, 31%), endometrium (9%), colon (9%), and stomach (6%). Approximately 43% of all mutations occur at two mutational "hotspots," which alter Arg residues (Arg465 and Arg479) that are critical for substrate recognition. Furthermore, we show that Fbxw7Arg465 hotspot mutant can abrogate wild-type Fbxw7 function through a dominant negative mechanism. Our study is the first comprehensive screen of FBXW7 mutations in various human malignancies and shows that FBXW7 is a general tumor suppressor in human cancer.
Place, publisher, year, edition, pages
2007. Vol. 67, no 19, 9006-9012 p.
5-Methylcytosine/metabolism, Amination, Cell Cycle Proteins/*genetics/metabolism, DNA Methylation, Dinucleotide Repeats, F-Box Proteins/*genetics/metabolism, Gene Expression Regulation; Neoplastic, Gene Silencing, Genes; Tumor Suppressor, Humans, Models; Molecular, Mutation, Neoplasms/*genetics/metabolism, Protein Isoforms, Substrate Specificity, Ubiquitin-Protein Ligases/*genetics/metabolism
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:uu:diva-15008DOI: 10.1158/0008-5472.CAN-07-1320ISI: 000249955500007PubMedID: 17909001OAI: oai:DiVA.org:uu-15008DiVA: diva2:42779