Abstract
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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 3964-3974 |
| Number of pages | 11 |
| Journal | Molecular and Cellular Biology |
| Volume | 29 |
| Issue number | 14 |
| DOIs | |
| State | Published - Jul 2009 |
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ASJC Scopus subject areas
- Molecular Biology
- Cell Biology
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Ral overactivation in malignant peripheral nerve sheath tumors. / Bodempudi, Vidya; Yamoutpoor, Farnaz; Pan, Weihong; Dudek, Arkadiusz Z.; Esfandyari, Tuba; Piedra, Mark; Babovick-Vuksanovic, Dusica; Woo, Richard A.; Mautner, Victor F.; Kluwe, Lan; Clapp, D. Wade; DeVries, George H.; Thomas, Stacey L.; Kurtz, Andreas; Parada, Luis F.; Farassati, Faris.
In: Molecular and Cellular Biology, Vol. 29, No. 14, 07.2009, p. 3964-3974.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Ral overactivation in malignant peripheral nerve sheath tumors
AU - Bodempudi, Vidya
AU - Yamoutpoor, Farnaz
AU - Pan, Weihong
AU - Dudek, Arkadiusz Z.
AU - Esfandyari, Tuba
AU - Piedra, Mark
AU - Babovick-Vuksanovic, Dusica
AU - Woo, Richard A.
AU - Mautner, Victor F.
AU - Kluwe, Lan
AU - Clapp, D. Wade
AU - DeVries, George H.
AU - Thomas, Stacey L.
AU - Kurtz, Andreas
AU - Parada, Luis F.
AU - Farassati, Faris
PY - 2009/7
Y1 - 2009/7
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=67650095150&partnerID=8YFLogxK
U2 - 10.1128/MCB.01153-08
DO - 10.1128/MCB.01153-08
M3 - Article
VL - 29
SP - 3964
EP - 3974
JO - Molecular and Cellular Biology
JF - Molecular and Cellular Biology
SN - 0270-7306
IS - 14
ER -