p190RhoGAP can act to inhibit PDGF-induced gliomas in mice: a putative tumor suppressor encoded on human Chromosome 19q13.3
- Rebecca M. Wolf1,4,
- Nicole Draghi1,5,
- Xiquan Liang1,
- Chengkai Dai1,2,3,4,
- Lene Uhrbom3,6,
- Charlotta Eklöf6,
- Bengt Westermark6,
- Eric C. Holland1,2,3,4, and
- Marilyn D. Resh1,4,5,7
- Departments of 1Cell Biology, 2Surgery, and 3Neurology, Memorial Sloan Kettering Cancer Center, New York, New York 10021, USA; 4Graduate Program in Cell Biology and Genetics and 5Biochemistry, Weill Graduate School of Medical Sciences of Cornell University, New York, New York 10021, USA; 6Department of Genetics and Pathology, Rudbeck Laboratory, SE-75185, Uppsala, Sweden
Abstract
p190RhoGAP and Rho are key regulators of oligodendrocyte differentiation. The gene encoding p190RhoGAP is located at 19q13.3 of the human chromosome, a locus that is deleted in 50%–80% of oligodendrogliomas. Here we provide evidence that p190RhoGAP may suppress gliomagenesis by inducing a differentiated glial phenotype. Using a cell culture model of autocrine loop PDGF stimulation, we show that reduced Rho activity via p190RhoGAP overexpression or Rho kinase inhibition induced cellular process extension, a block in proliferation, and reduced expression of the neural precursor marker nestin. In vivo infection of mice with retrovirus expressing PDGF and the p190 GAP domain caused a decreased incidence of oligodendrogliomas compared with that observed with PDGF alone. Independent experiments revealed that the retroviral vector insertion site in 3 of 50 PDGF-induced gliomas was within the p190RhoGAP gene. This evidence strongly suggests that p190 regulates critical components of PDGF oncogenesis and can act as a tumor suppressor in PDGF-induced gliomas by down-regulating Rho activity.
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Footnotes
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↵7 Corresponding author.
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E-MAIL m-resh{at}ski.mskcc.org; FAX (212) 717-3317.
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Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/gad.1040003.
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- Received September 9, 2002.
- Accepted January 9, 2003.
- Cold Spring Harbor Laboratory Press