FBXW7/hCDC4 is a general tumor suppressor in human cancer.
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.
Akhoondi
Shahab
S
Cancer Center Karolinska, Karolinska Hospital, Stockholm, Sweden.
Sun
Dahui
D
von der Lehr
Natalie
N
Apostolidou
Sophia
S
Klotz
Kathleen
K
Maljukova
Alena
A
Cepeda
Diana
D
Fiegl
Heidi
H
Dafou
Dimitra
D
Dofou
Dimitra
D
Marth
Christian
C
Mueller-Holzner
Elisabeth
E
Corcoran
Martin
M
Dagnell
Markus
M
Nejad
Sepideh Zabihi
SZ
Nayer
Babak Noori
BN
Zali
Mohammad Reza
MR
Hansson
Johan
J
Egyhazi
Susanne
S
Petersson
Fredrik
F
Sangfelt
Per
P
Nordgren
Hans
H
Grander
Dan
D
Reed
Steven I
SI
Widschwendter
Martin
M
Sangfelt
Olle
O
Spruck
Charles
C
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
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