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Article: Deleted in liver cancer 2 (DLC2) suppresses cell transformation by means of inhibition of RhoA activity
Title | Deleted in liver cancer 2 (DLC2) suppresses cell transformation by means of inhibition of RhoA activity |
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Authors | |
Issue Date | 2005 |
Publisher | National 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? |
Abstract | The 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 Identifier | http://hdl.handle.net/10722/68200 |
ISSN | 2023 Impact Factor: 9.4 2023 SCImago Journal Rankings: 3.737 |
ISI Accession Number ID | |
References |
DC Field | Value | Language |
---|---|---|
dc.contributor.author | Leung, THY | en_HK |
dc.contributor.author | Ching, YP | en_HK |
dc.contributor.author | Yam, JWP | en_HK |
dc.contributor.author | Wong, CM | en_HK |
dc.contributor.author | Yau, TO | en_HK |
dc.contributor.author | Jin, DY | en_HK |
dc.contributor.author | Ng, IOL | en_HK |
dc.date.accessioned | 2010-09-06T06:02:19Z | - |
dc.date.available | 2010-09-06T06:02:19Z | - |
dc.date.issued | 2005 | en_HK |
dc.identifier.citation | Proceedings of the National Academy of Sciences of The United States of America, 2005, v. 102 n. 42, p. 15207-15212 | en_HK |
dc.identifier.issn | 0027-8424 | en_HK |
dc.identifier.uri | http://hdl.handle.net/10722/68200 | - |
dc.description.abstract | The 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.language | eng | en_HK |
dc.publisher | National Academy of Sciences. The Journal's web site is located at http://www.pnas.org | en_HK |
dc.relation.ispartof | Proceedings of the National Academy of Sciences of the United States of America | en_HK |
dc.rights | Proceedings of the National Academy of Sciences. Copyright © National Academy of Sciences. | en_HK |
dc.subject.mesh | 3T3 Cells | en_HK |
dc.subject.mesh | Actins - metabolism | en_HK |
dc.subject.mesh | Animals | en_HK |
dc.subject.mesh | Cell Movement | en_HK |
dc.subject.mesh | Cell Proliferation | en_HK |
dc.subject.mesh | Cell Shape | en_HK |
dc.subject.mesh | Cell Transformation, Neoplastic | en_HK |
dc.subject.mesh | Fibroblasts - cytology - physiology | en_HK |
dc.subject.mesh | GTPase-Activating Proteins - genetics - metabolism | en_HK |
dc.subject.mesh | Humans | en_HK |
dc.subject.mesh | Mice | en_HK |
dc.subject.mesh | Molecular Sequence Data | en_HK |
dc.subject.mesh | Protein Isoforms - genetics - metabolism | en_HK |
dc.subject.mesh | Tumor Suppressor Proteins - genetics - metabolism | en_HK |
dc.subject.mesh | rhoA GTP-Binding Protein - antagonists & inhibitors - metabolism | en_HK |
dc.title | Deleted in liver cancer 2 (DLC2) suppresses cell transformation by means of inhibition of RhoA activity | en_HK |
dc.type | Article | en_HK |
dc.identifier.openurl | http://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.email | Ching, YP:ypching@hku.hk | en_HK |
dc.identifier.email | Yam, JWP:judyyam@pathology.hku.hk | en_HK |
dc.identifier.email | Wong, CM:jackwong@pathology.hku.hk | en_HK |
dc.identifier.email | Jin, DY:dyjin@hkucc.hku.hk | en_HK |
dc.identifier.email | Ng, IOL:iolng@hkucc.hku.hk | en_HK |
dc.identifier.authority | Ching, YP=rp00469 | en_HK |
dc.identifier.authority | Yam, JWP=rp00468 | en_HK |
dc.identifier.authority | Wong, CM=rp00231 | en_HK |
dc.identifier.authority | Jin, DY=rp00452 | en_HK |
dc.identifier.authority | Ng, IOL=rp00335 | en_HK |
dc.description.nature | link_to_OA_fulltext | - |
dc.identifier.doi | 10.1073/pnas.0504501102 | en_HK |
dc.identifier.pmid | 16217026 | - |
dc.identifier.scopus | eid_2-s2.0-27244455897 | en_HK |
dc.identifier.hkuros | 129318 | en_HK |
dc.identifier.hkuros | 113952 | - |
dc.relation.references | http://www.scopus.com/mlt/select.url?eid=2-s2.0-27244455897&selection=ref&src=s&origin=recordpage | en_HK |
dc.identifier.volume | 102 | en_HK |
dc.identifier.issue | 42 | en_HK |
dc.identifier.spage | 15207 | en_HK |
dc.identifier.epage | 15212 | en_HK |
dc.identifier.isi | WOS:000232811800049 | - |
dc.publisher.place | United States | en_HK |
dc.identifier.scopusauthorid | Leung, THY=7202110922 | en_HK |
dc.identifier.scopusauthorid | Ching, YP=7005431277 | en_HK |
dc.identifier.scopusauthorid | Yam, JWP=6603711123 | en_HK |
dc.identifier.scopusauthorid | Wong, CM=16314668400 | en_HK |
dc.identifier.scopusauthorid | Yau, TO=7006540669 | en_HK |
dc.identifier.scopusauthorid | Jin, DY=7201973614 | en_HK |
dc.identifier.scopusauthorid | Ng, IOL=7102753722 | en_HK |
dc.identifier.issnl | 0027-8424 | - |