p190RhoGAP can act to inhibit PDGF-induced gliomas in mice: A putative tumor suppressor encoded on human Chromosome 19q13.3 Journal Article

   

Authors:	Wolf, R. M.; Draghi, N.; Liang, X.; Dai, C.; Uhrbom, L.; Eklöf, C.; Westermark, B.; Holland, E. C.; Resh, M. D.
Article Title:	p190RhoGAP can act to inhibit PDGF-induced gliomas in mice: A putative tumor suppressor encoded on human Chromosome 19q13.3
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.
Keywords:	platelet derived growth factor; controlled study; unclassified drug; human cell; gene deletion; dna-binding proteins; pathogenesis; nonhuman; pyridines; glioma; brain neoplasms; protein domain; cell proliferation; animal cell; mouse; phenotype; animals; mice; cells, cultured; enzyme inhibition; embryo; animal experiment; animal model; nerve tissue proteins; down-regulation; gene locus; gene product; in vivo study; cell differentiation; carcinogenesis; animalia; nuclear proteins; mice, inbred strains; gene expression regulation; tumor suppressor gene; drug mechanism; cell culture; newborn; platelet-derived growth factor; retrovirus vector; chromosomes, human, pair 19; gtpase-activating proteins; oligodendroglioma; down regulation; gene insertion; nerve cell differentiation; repressor proteins; nestin; genetic code; intermediate filament proteins; phosphotransferase inhibitor; genes, tumor suppressor; retroviridae; gene activity; rho kinase; guanine nucleotide exchange factors; phthalazines; rhoa; oligodendroglia; chromosome 19q; unidentified retrovirus; 4 (1 aminoethyl) n (4 pyridyl)cyclohexanecarboxamide; humans; human; priority journal; article; p190rhogap; protein p190rhogap
Journal Title:	Genes and Development
Volume:	17
Issue:	4
ISSN:	0890-9369
Publisher:	Cold Spring Harbor Laboratory Press
Date Published:	2003-02-15
Start Page:	476
End Page:	487
Language:	English
DOI:	10.1101/gad.1040003
PUBMED:	12600941
PROVIDER:	scopus
PMCID:	PMC196001
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-0037442818&partnerID=40&md5=6b4e2cd25345e8d52b6f585074036f1e
Notes:	Export Date: 12 September 2014 -- Molecular Sequence Numbers: AC073790, AF159851, M94721; -- Source: Scopus

https://synapse.mskcc.org/synapse/works/has_related_data_chk/60189