title: FBXW7/hCDC4 is a general tumor suppressor in human cancer.
abstract: 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 (Skp1-Cdc53/Cullin-F-box-protein), has been shown to mediate the ubiquitin-dependent proteolysis of several oncoproteins including cyclin E1, 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 approximately 6%. The highest mutation frequencies were found in tumors of the bile duct (cholangiocarcinomas, 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.
authors.affiliation: Cancer Center Karolinska, Karolinska Hospital, Stockholm, Sweden.
authors.forename: Shahab
authors.initials: S
authors.lastname: Akhoondi
authors.forename: Dahui
authors.initials: D
authors.lastname: Sun
authors.forename: Natalie
authors.initials: N
authors.lastname: von der Lehr
authors.forename: Sophia
authors.initials: S
authors.lastname: Apostolidou
authors.forename: Kathleen
authors.initials: K
authors.lastname: Klotz
authors.forename: Alena
authors.initials: A
authors.lastname: Maljukova
authors.forename: Diana
authors.initials: D
authors.lastname: Cepeda
authors.forename: Heidi
authors.initials: H
authors.lastname: Fiegl
authors.forename: Dimitra
authors.initials: D
authors.lastname: Dafou
authors.forename: Dimitra
authors.initials: D
authors.lastname: Dofou
authors.forename: Christian
authors.initials: C
authors.lastname: Marth
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Mueller-Holzner
authors.forename: Martin
authors.initials: M
authors.lastname: Corcoran
authors.forename: Markus
authors.initials: M
authors.lastname: Dagnell
authors.forename: Sepideh Zabihi
authors.initials: SZ
authors.lastname: Nejad
authors.forename: Babak Noori
authors.initials: BN
authors.lastname: Nayer
authors.forename: Mohammad Reza
authors.initials: MR
authors.lastname: Zali
authors.forename: Johan
authors.initials: J
authors.lastname: Hansson
authors.forename: Susanne
authors.initials: S
authors.lastname: Egyhazi
authors.forename: Fredrik
authors.initials: F
authors.lastname: Petersson
authors.forename: Per
authors.initials: P
authors.lastname: Sangfelt
authors.forename: Hans
authors.initials: H
authors.lastname: Nordgren
authors.forename: Dan
authors.initials: D
authors.lastname: Grander
authors.forename: Steven I
authors.initials: SI
authors.lastname: Reed
authors.forename: Martin
authors.initials: M
authors.lastname: Widschwendter
authors.forename: Olle
authors.initials: O
authors.lastname: Sangfelt
authors.forename: Charles
authors.initials: C
authors.lastname: Spruck
mesh_terms: D044503:5-Methylcytosine / Q000378:metabolism; D000586:Amination; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D018900:Dinucleotide Repeats; D044783:F-Box Proteins / Q000235:genetics* / Q000378:metabolism; D000073979:F-Box-WD Repeat-Containing Protein 7; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism; D020033:Protein Isoforms; D013379:Substrate Specificity; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; D020033:Protein Isoforms; D044503:5-Methylcytosine; D044767:Ubiquitin-Protein Ligases