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Molecular and Cellular Biology, July 2009, p. 3964-3974, Vol. 29, No. 14
0270-7306/09/$08.00+0     doi:10.1128/MCB.01153-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Ral Overactivation in Malignant Peripheral Nerve Sheath Tumors{triangledown}

Vidya Bodempudi,2 Farnaz Yamoutpoor,2 Weihong Pan,2 Arkadiusz Z. Dudek,2 Tuba Esfandyari,1 Mark Piedra,3 Dusica Babovick-Vuksanovic,3 Richard A. Woo,4 Victor F. Mautner,5 Lan Kluwe,5 D. Wade Clapp,6 George H. De Vries,7 Stacey L. Thomas,7 Andreas Kurtz,8 Luis F. Parada,9 and Faris Farassati1*

Molecular Medicine Laboratory, University of Kansas School of Medicine, Department of Medicine, Kansas City, Kansas,1 University of Minnesota, Minneapolis, Minnesota,2 Mayo Clinic, Rochester, Minnesota,3 Southern Illinois University, Springfield, Illinois,4 University Hospital Eppendorf, Hamburg, Germany,5 University of Indiana School of Medicine, Indianapolis, Indiana,6 Research Service, Edward Hines, Jr., V.A. Hospital, Hines, Illinois,7 Massachusetts General Hospital, Charlestown, Massachusetts,8 University of Texas Southwestern Medical Center, Dallas, Texas9

Received 21 July 2008/ Returned for modification 8 September 2008/ Accepted 30 March 2009

Ras leads an important signaling pathway that is deregulated in neurofibromatosis type 1 and malignant peripheral nerve sheath tumor (MPNST). In this study, we show that overactivation of Ras and many of its downstream effectors occurred in only a fraction of MPNST cell lines. RalA, however, was overactivated in all MPNST cells and tumor samples compared to nontransformed Schwann cells. Silencing Ral or inhibiting it with a dominant-negative Ral (Ral S28N) caused a significant reduction in proliferation, invasiveness, and in vivo tumorigenicity of MPNST cells. Silencing Ral also reduced the expression of epithelial mesenchymal transition markers. Expression of the NF1-GTPase-related domain (NF1-GRD) diminished the levels of Ral activation, implicating a role for neurofibromin in regulating RalA activation. NF1-GRD treatment caused a significant decrease in proliferation, invasiveness, and cell cycle progression, but cell death increased. We propose Ral overactivation as a novel cell signaling abnormality in MPNST that leads to important biological outcomes with translational ramifications.

* Corresponding author. Mailing address: KUMC-Molecular Medicine Laboratory, 1000 Hixon, Mail Stop 4037, 3901 Rainbow Blvd., Kansas City, KS 66160. Phone: (913) 945-6823. Fax: (913) 945-6923. E-mail: ffarassati{at}kumc.edu

{triangledown} Published ahead of print on 4 May 2009.

Molecular and Cellular Biology, July 2009, p. 3964-3974, Vol. 29, No. 14
0270-7306/09/$08.00+0     doi:10.1128/MCB.01153-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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