p190RhoGAP can act to inhibit PDGF-induced gliomas in mice: a putative tumor suppressor encoded on human chromosome 19q13.3.

Document Type

Article

Publication Date

2003

Keywords

Brain-Neoplasms, Cell-Differentiation, Cells-Cultured, Chromosomes-Human-Pair-19, DNA-Binding-Proteins, Down-Regulation, GTPase-Activating-Proteins, Genes-Tumor-Suppressor, Glioma, Guanine-Nucleotide-Exchange-Factors, Intermediate-Filament-Proteins, Mice-Inbred-Strains, Nerve-Tissue-Proteins, Nuclear-Proteins, Oligodendroglioma, Phthalazines, Platelet-Derived-Growth-Factor, Pyridines, Repressor-Proteins, Retroviridae

First Page

476

Last Page

487

JAX Source

Genes Dev 2003 Feb; 17(4):476-87.

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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