p190RhoGAP can act to inhibit PDGF-induced gliomas in mice: a putative tumor suppressor encoded on human chromosome 19q13.3.
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.
Wolf
Rebecca M
RM
Department of Cell Biology, Memorial Sloan Kettering Cancer Center, New York, New York 10021, USA.
Draghi
Nicole
N
Liang
Xiquan
X
Dai
Chengkai
C
Uhrbom
Lene
L
Eklöf
Charlotta
C
Westermark
Bengt
B
Holland
Eric C
EC
Resh
Marilyn D
MD
D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics / Q000473:pathology*; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D002888:Chromosomes, Human, Pair 19; D004268:DNA-Binding Proteins; D015536:Down-Regulation; D020690:GTPase-Activating Proteins; D016147:Genes, Tumor Suppressor; D005910:Glioma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007381:Intermediate Filament Proteins / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D009419:Nerve Tissue Proteins; D064231:Nestin; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D009837:Oligodendroglioma / Q000235:genetics / Q000473:pathology; D010793:Phthalazines / Q000494:pharmacology; D010982:Platelet-Derived Growth Factor / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D011725:Pyridines; D012097:Repressor Proteins; D012190:Retroviridae / Q000235:genetics
C074560:ARHGAP35 protein, human; C513043:ARHGAP5 protein, human; C513041:Arhgap35 protein, mouse; C513042:Arhgap5 protein, mouse; D004268:DNA-Binding Proteins; D020690:GTPase-Activating Proteins; D020662:Guanine Nucleotide Exchange Factors; D007381:Intermediate Filament Proteins; C577484:NES protein, human; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; D009687:Nuclear Proteins; D010793:Phthalazines; D010982:Platelet-Derived Growth Factor; D011725:Pyridines; D012097:Repressor Proteins; C404768:vatalanib