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- Shahab Akhoondi
- 1Cancer Center Karolinska, Karolinska Hospital, Stockholm, Sweden;
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- Dahui Sun
- 2Department of Tumor Cell Biology, Sidney Kimmel Cancer Center, San Diego, California;
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- Natalie von der Lehr
- 1Cancer Center Karolinska, Karolinska Hospital, Stockholm, Sweden;
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- Sophia Apostolidou
- 3Department of Gynaecological Oncology, Institute for Women's Health, University College London, London, United Kingdom;
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- Kathleen Klotz
- 2Department of Tumor Cell Biology, Sidney Kimmel Cancer Center, San Diego, California;
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- Alena Maljukova
- 1Cancer Center Karolinska, Karolinska Hospital, Stockholm, Sweden;
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- Diana Cepeda
- 1Cancer Center Karolinska, Karolinska Hospital, Stockholm, Sweden;
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- Heidi Fiegl
- 3Department of Gynaecological Oncology, Institute for Women's Health, University College London, London, United Kingdom;
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- Dimitra Dofou
- 3Department of Gynaecological Oncology, Institute for Women's Health, University College London, London, United Kingdom;
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- Christian Marth
- 4Department of Obstetrics and Gynecology, Medical University Innsbruck, Innsbruck, Austria;
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- Elisabeth Mueller-Holzner
- 4Department of Obstetrics and Gynecology, Medical University Innsbruck, Innsbruck, Austria;
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- Martin Corcoran
- 1Cancer Center Karolinska, Karolinska Hospital, Stockholm, Sweden;
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- Markus Dagnell
- 1Cancer Center Karolinska, Karolinska Hospital, Stockholm, Sweden;
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- Sepideh Zabihi Nejad
- 5Research Center for Gastrointestinal and Liver Disease, Taleghani Hospital, Tehran, Iran;
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- Babak Noori Nayer
- 5Research Center for Gastrointestinal and Liver Disease, Taleghani Hospital, Tehran, Iran;
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- Mohammad Reza Zali
- 5Research Center for Gastrointestinal and Liver Disease, Taleghani Hospital, Tehran, Iran;
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- Johan Hansson
- 1Cancer Center Karolinska, Karolinska Hospital, Stockholm, Sweden;
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- Susanne Egyhazi
- 1Cancer Center Karolinska, Karolinska Hospital, Stockholm, Sweden;
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- Fredrik Petersson
- 1Cancer Center Karolinska, Karolinska Hospital, Stockholm, Sweden;
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- Per Sangfelt
- 6Department of Medical Sciences, Pathology, and Gastroenterology, Uppsala University Hospital, Uppsala, Sweden; and
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- Hans Nordgren
- 6Department of Medical Sciences, Pathology, and Gastroenterology, Uppsala University Hospital, Uppsala, Sweden; and
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- Dan Grander
- 1Cancer Center Karolinska, Karolinska Hospital, Stockholm, Sweden;
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- Steven I. Reed
- 7Department of Molecular Biology, The Scripps Research Institute, La Jolla, California
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- Martin Widschwendter
- 3Department of Gynaecological Oncology, Institute for Women's Health, University College London, London, United Kingdom;
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- Olle Sangfelt
- 1Cancer Center Karolinska, Karolinska Hospital, Stockholm, Sweden;
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- Charles Spruck
- 2Department of Tumor Cell Biology, Sidney Kimmel Cancer Center, San Diego, California;
説明
<jats:title>Abstract</jats:title> <jats:p>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 ∼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. [Cancer Res 2007;67(19):9006–12]</jats:p>
収録刊行物
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- Cancer Research
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Cancer Research 67 (19), 9006-9012, 2007-10-01
American Association for Cancer Research (AACR)
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詳細情報 詳細情報について
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- CRID
- 1363107369933345408
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- ISSN
- 15387445
- 00085472
- http://id.crossref.org/issn/00085472
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- データソース種別
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- Crossref