Ral overactivation in malignant peripheral nerve sheath tumors.
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.
Bodempudi
Vidya
V
Department of Medicine, KUMC-Molecular Medicine Laboratory, University of Kansas School of Medicine, 1000 Hixon, Mail Stop 4037, 3901 Rainbow Blvd., Kansas City, KS 66160, USA.
Yamoutpoor
Farnaz
F
Pan
Weihong
W
Dudek
Arkadiusz Z
AZ
Esfandyari
Tuba
T
Piedra
Mark
M
Babovick-Vuksanovic
Dusica
D
Woo
Richard A
RA
Mautner
Victor F
VF
Kluwe
Lan
L
Clapp
D Wade
DW
De Vries
George H
GH
Thomas
Stacey L
SL
Kurtz
Andreas
A
Parada
Luis F
LF
Farassati
Faris
F
D000818:Animals; D001483:Base Sequence; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D018317:Nerve Sheath Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D012583:Schwann Cells / Q000378:metabolism; D015398:Signal Transduction; D015533:Transcriptional Activation; D020725:ral GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism
D034741:RNA, Small Interfering; C492198:RALA protein, human; C118120:Rala protein, mouse; D020725:ral GTP-Binding Proteins; D018631:ras Proteins