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Molecular and Cellular Biology, January 2008, p. 743-751, Vol. 28, No. 2
0270-7306/08/$08.00+0     doi:10.1128/MCB.01665-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Disruption of the Fbxw8 Gene Results in Pre- and Postnatal Growth Retardation in Mice{triangledown} ,{dagger}

Takeya Tsutsumi,1,2 Hiroshi Kuwabara,1,2 Takehiro Arai,1,2 Yonghong Xiao,3 and James A. DeCaprio1,2,3*

Department of Medical Oncology, Dana-Farber Cancer Institute,1 Department of Medicine, Brigham and Women's Hospital,2 Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts3

Received 8 September 2007/ Returned for modification 22 October 2007/ Accepted 30 October 2007

CUL7 binds to SKP1, RBX1, and FBXW8 to form a cullin-RING ligase, or an SKP1-cullin-F box protein complex. The targeted disruption of the Cul7 gene in mice results in significant reduction in embryo size and neonatal lethality. In humans, CUL7 was found to be mutated in the 3-M dwarfism syndrome characterized by severe pre- and postnatal growth retardation, indicating that CUL7 is closely associated with human and mouse growth. We generated mice lacking Fbxw8 by gene trapping. Similar to Cul7–/– animals, Fbxw8–/– embryos and placentas were smaller than wild-type and heterozygous littermates and placentas. Approximately 30% of the expected number of Fbxw8–/– mice survived birth, but these mice remained smaller than their wild-type and heterozygous littermates throughout postnatal development. FBXW8 expression was detected in most organs of wild-type mice examined, and the organs in Fbxw8–/– mice were smaller than those in wild-type mice. Fbxw8 expression levels were highest in skeletal muscle, cartilage, and lung tissue. Expression profiling revealed elevated levels of insulin-like growth factor binding protein 1 (IGFBP1) transcripts in Fbxw8–/– embryos. Furthermore, we observed increased levels of IGFBP2 in Cul7–/– as well as Fbxw8–/– fibroblasts. These results demonstrate that the FBXW8-CUL7 complex plays a significant role in growth control.

* Corresponding author. Mailing address: Dana-Farber Cancer Institute, 44 Binney St., Boston, MA 02115. Phone: (617) 632-3825. Fax: (617) 582-8601. E-mail: james_decaprio{at}dfci.harvard.edu

{triangledown} Published ahead of print on 12 November 2007.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, January 2008, p. 743-751, Vol. 28, No. 2
0270-7306/08/$08.00+0     doi:10.1128/MCB.01665-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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