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FBXW7/hCDC4 Is a General Tumor Suppressor in Human Cancer

¹ Cancer Center Karolinska, Karolinska Hospital, Stockholm, Sweden; ² Department of Tumor Cell Biology, Sidney Kimmel Cancer Center, San Diego, California; ³ Department of Gynaecological Oncology, Institute for Women's Health, University College London, London, United Kingdom; ⁴ Department of Obstetrics and Gynecology, Medical University Innsbruck, Innsbruck, Austria; ⁵ Research Center for Gastrointestinal and Liver Disease, Taleghani Hospital, Tehran, Iran; ⁶ Department of Medical Sciences, Pathology, and Gastroenterology, Uppsala University Hospital, Uppsala, Sweden; and ⁷ Department of Molecular Biology, The Scripps Research Institute, La Jolla, California

Requests for reprints: Charles Spruck, Sidney Kimmel Cancer Center, 10905 Road to the Cure, San Diego, CA 92121. Phone: 858-450-5990; Fax: 858-450-3251; E-mail: cspruck{at}skcc.org.

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 Fbxw7^Arg465 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]

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				Correction: The FBXW7 Gene Is Mutated in a Variety of Human Tumors Cancer Res., February 15, 2008; 68(4): 1245 - 1245. [Full Text] [PDF]