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Fbxw7/hcdc4 is a general tumor suppressor in human cancer

Academic Article
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Overview

authors

  • Akhoondi, S.
  • Sun, D.
  • von der Lehr, N.
  • Apostolidou, S.
  • Klotz, K.
  • Maljukova, A.
  • Cepeda, D.
  • Fiegl, H.
  • Dofou, D.
  • Marth, C.
  • Mueller-Holzner, E.
  • Corcoran, M.
  • Dagnell, M.
  • Nejad, S. Z.
  • Nayer, B. N.
  • Zali, M. R.
  • Hansson, J.
  • Egyhazi, S.
  • Petersson, F.
  • Sangfelt, P.
  • Nordgren, H.
  • Grander, D.
  • Reed, Steven
  • Widschwendter, M.
  • Sangfelt, O.
  • Spruck, C.

publication date

  • October 2007

journal

  • Cancer Research  Journal

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.

subject areas

  • 5-Methylcytosine
  • Amination
  • Cell Cycle Proteins
  • DNA Methylation
  • Dinucleotide Repeats
  • F-Box Proteins
  • Gene Expression Regulation, Neoplastic
  • Gene Silencing
  • Genes, Tumor Suppressor
  • Humans
  • Models, Molecular
  • Mutation
  • Neoplasms
  • Protein Isoforms
  • Substrate Specificity
  • Ubiquitin-Protein Ligases
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Identity

International Standard Serial Number (ISSN)

  • 0008-5472

Digital Object Identifier (DOI)

  • 10.1158/0008-5472.can-07-1320

PubMed ID

  • 17909001
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Additional Document Info

start page

  • 9006

end page

  • 9012

volume

  • 67

issue

  • 19

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