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Article: Deleted in liver cancer 2 (DLC2) suppresses cell transformation by means of inhibition of RhoA activity

TitleDeleted in liver cancer 2 (DLC2) suppresses cell transformation by means of inhibition of RhoA activity
Authors
Issue Date2005
PublisherNational Academy of Sciences. The Journal's web site is located at http://www.pnas.org
Citation
Proceedings of the National Academy of Sciences of The United States of America, 2005, v. 102 n. 42, p. 15207-15212 How to Cite?
AbstractThe deleted in liver cancer 2 (DLC2) gene, located at chromosome 13q12.3, is a recently identified tumor suppressor gene. The gene is frequently underexpressed in human hepatocellular carcinoma, and its chromosomal region shows frequent deletion. DLC2 encodes a unique RhoGTPase-activating protein (RhoGAP) specific for small RhoGTPases, RhoA, and Cdc42. With bioinformatic analysis, we have identified four different isoforms of DLC2, which we named DLC2α, DLC2β, DLC2γ, and DLC2δ. Three of the isoforms contain the RhoGAP domain, namely, DLC2α, DLC2β, and DLC2γ. Ectopic expression of these three isoforms in mouse fibroblasts showed cytoplasmic localization. Of interest, overexpression of these isoforms suppressed the lysophosphatidic acid-induced stress fiber formation in mouse fibroblasts and changed the morphology of the transfected cells from angular and spindle to round. Furthermore, the RhoA pull-down assay demonstrated a remarkable reduction in RhoA activity in the DLC2 transiently transfected cells. In contrast, cells transfected with inactive DLC2 GAP-mutant remained unchanged in cell morphology, actin stress fiber formation, and RhoA activity. HepG2 hepatoma cells stably transfected with the DLC2γ isoform also changed to a round morphology, as in mouse fibroblasts. Of significance, these DLC2γ stable transfectants showed marked suppression in cell proliferation, motility, and transformation, and there was a remarkable reduction in in vivo RhoA activity in these cells. These results suggest that DLC2 exhibits its tumor suppressor functions in vivo as a GAP specific for RhoA, exerting its effects in suppression of cytoskeleton reorganization, cell growth, cell migration, and transformation. © 2005 by The National Academy of Sciences of the USA.
Persistent Identifierhttp://hdl.handle.net/10722/68200
ISSN
2015 Impact Factor: 9.423
2015 SCImago Journal Rankings: 6.883
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorLeung, THYen_HK
dc.contributor.authorChing, YPen_HK
dc.contributor.authorYam, JWPen_HK
dc.contributor.authorWong, CMen_HK
dc.contributor.authorYau, TOen_HK
dc.contributor.authorJin, DYen_HK
dc.contributor.authorNg, IOLen_HK
dc.date.accessioned2010-09-06T06:02:19Z-
dc.date.available2010-09-06T06:02:19Z-
dc.date.issued2005en_HK
dc.identifier.citationProceedings of the National Academy of Sciences of The United States of America, 2005, v. 102 n. 42, p. 15207-15212en_HK
dc.identifier.issn0027-8424en_HK
dc.identifier.urihttp://hdl.handle.net/10722/68200-
dc.description.abstractThe deleted in liver cancer 2 (DLC2) gene, located at chromosome 13q12.3, is a recently identified tumor suppressor gene. The gene is frequently underexpressed in human hepatocellular carcinoma, and its chromosomal region shows frequent deletion. DLC2 encodes a unique RhoGTPase-activating protein (RhoGAP) specific for small RhoGTPases, RhoA, and Cdc42. With bioinformatic analysis, we have identified four different isoforms of DLC2, which we named DLC2α, DLC2β, DLC2γ, and DLC2δ. Three of the isoforms contain the RhoGAP domain, namely, DLC2α, DLC2β, and DLC2γ. Ectopic expression of these three isoforms in mouse fibroblasts showed cytoplasmic localization. Of interest, overexpression of these isoforms suppressed the lysophosphatidic acid-induced stress fiber formation in mouse fibroblasts and changed the morphology of the transfected cells from angular and spindle to round. Furthermore, the RhoA pull-down assay demonstrated a remarkable reduction in RhoA activity in the DLC2 transiently transfected cells. In contrast, cells transfected with inactive DLC2 GAP-mutant remained unchanged in cell morphology, actin stress fiber formation, and RhoA activity. HepG2 hepatoma cells stably transfected with the DLC2γ isoform also changed to a round morphology, as in mouse fibroblasts. Of significance, these DLC2γ stable transfectants showed marked suppression in cell proliferation, motility, and transformation, and there was a remarkable reduction in in vivo RhoA activity in these cells. These results suggest that DLC2 exhibits its tumor suppressor functions in vivo as a GAP specific for RhoA, exerting its effects in suppression of cytoskeleton reorganization, cell growth, cell migration, and transformation. © 2005 by The National Academy of Sciences of the USA.en_HK
dc.languageengen_HK
dc.publisherNational Academy of Sciences. The Journal's web site is located at http://www.pnas.orgen_HK
dc.relation.ispartofProceedings of the National Academy of Sciences of the United States of Americaen_HK
dc.rightsProceedings of the National Academy of Sciences. Copyright © National Academy of Sciences.en_HK
dc.subject.mesh3T3 Cellsen_HK
dc.subject.meshActins - metabolismen_HK
dc.subject.meshAnimalsen_HK
dc.subject.meshCell Movementen_HK
dc.subject.meshCell Proliferationen_HK
dc.subject.meshCell Shapeen_HK
dc.subject.meshCell Transformation, Neoplasticen_HK
dc.subject.meshFibroblasts - cytology - physiologyen_HK
dc.subject.meshGTPase-Activating Proteins - genetics - metabolismen_HK
dc.subject.meshHumansen_HK
dc.subject.meshMiceen_HK
dc.subject.meshMolecular Sequence Dataen_HK
dc.subject.meshProtein Isoforms - genetics - metabolismen_HK
dc.subject.meshTumor Suppressor Proteins - genetics - metabolismen_HK
dc.subject.meshrhoA GTP-Binding Protein - antagonists & inhibitors - metabolismen_HK
dc.titleDeleted in liver cancer 2 (DLC2) suppresses cell transformation by means of inhibition of RhoA activityen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0027-8424&volume=102&spage=15207&epage=15212&date=2005&atitle=Deleted+in+liver+cancer+2+(DLC2)+suppresses+cell+transformation+by+means+of+inhibition+of+RhoA+activity.en_HK
dc.identifier.emailChing, YP:ypching@hku.hken_HK
dc.identifier.emailYam, JWP:judyyam@pathology.hku.hken_HK
dc.identifier.emailWong, CM:jackwong@pathology.hku.hken_HK
dc.identifier.emailJin, DY:dyjin@hkucc.hku.hken_HK
dc.identifier.emailNg, IOL:iolng@hkucc.hku.hken_HK
dc.identifier.authorityChing, YP=rp00469en_HK
dc.identifier.authorityYam, JWP=rp00468en_HK
dc.identifier.authorityWong, CM=rp00231en_HK
dc.identifier.authorityJin, DY=rp00452en_HK
dc.identifier.authorityNg, IOL=rp00335en_HK
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1073/pnas.0504501102en_HK
dc.identifier.pmid16217026-
dc.identifier.scopuseid_2-s2.0-27244455897en_HK
dc.identifier.hkuros129318en_HK
dc.identifier.hkuros113952-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-27244455897&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume102en_HK
dc.identifier.issue42en_HK
dc.identifier.spage15207en_HK
dc.identifier.epage15212en_HK
dc.identifier.isiWOS:000232811800049-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridLeung, THY=7202110922en_HK
dc.identifier.scopusauthoridChing, YP=7005431277en_HK
dc.identifier.scopusauthoridYam, JWP=6603711123en_HK
dc.identifier.scopusauthoridWong, CM=16314668400en_HK
dc.identifier.scopusauthoridYau, TO=7006540669en_HK
dc.identifier.scopusauthoridJin, DY=7201973614en_HK
dc.identifier.scopusauthoridNg, IOL=7102753722en_HK

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