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Article: Nuclear-targeted deleted in liver cancer 1 (DLC1) is less efficient in exerting its tumor suppressive activity both in vitro and in vivo

TitleNuclear-targeted deleted in liver cancer 1 (DLC1) is less efficient in exerting its tumor suppressive activity both in vitro and in vivo
Authors
Issue Date2011
PublisherPublic Library of Science. The Journal's web site is located at http://www.plosone.org/home.action
Citation
PLoS One, 2011, v. 6 n. 9, article no. e25547 How to Cite?
AbstractBACKGROUND: Deleted in liver cancer 1 (DLC1) serves as an important RhoGTPase activating protein (RhoGAP) protein that terminates active RhoA signaling in human cancers. Increasing evidence has demonstrated that the tumor suppressive activity of DLC1 depends not only on RhoGAP activity, but also relies on proper focal adhesion localization through its interaction with tensin family proteins. Recently, there are reports showing that DLC1 can also be found in the nucleus; however, the existence and the relative tumor suppressive activity of nuclear DLC1 have never been clearly addressed. METHODOLOGY AND PRINCIPAL FINDINGS: We herein provide new evidence that DLC1 protein, which predominantly associated with focal adhesions and localized in cytosol, dynamically shuttled between cytoplasm and nucleus. Treatment of cells with nuclear export blocker, Leptomycin B (LMB), retained DLC1 in the nucleus. To understand the nuclear entry of DLC1, we identified amino acids 600-700 of DLC1 as a novel region that is important for its nuclear localization. The tumor suppressive activity of nuclear DLC1 was directly assessed by employing a nuclear localization signal (NLS) fusion variant of DLC1 (NLS-DLC1) with preferential nuclear localization. In SMMC-7721 HCC cells, expression of NLS-DLC1 failed to suppress colony formation and actin stress fiber formation in vitro. The abrogated tumor suppressive activity of nuclear DLC1 was demonstrated for the first time in vivo by subcutaneously injecting p53(-/-) RasV12 hepatoblasts with stable NLS-DLC1 expression in nude mice. The injected hepatoblasts with NLS-DLC1 expression effectively formed tumors when compared with the non-nuclear targeted DLC1. CONCLUSIONS/SIGNIFICANCE: Our study identified a novel region responsible for the nuclear entry of DLC1 and demonstrated the functional difference of DLC1 in different cellular compartments both in vitro and in vivo.
Persistent Identifierhttp://hdl.handle.net/10722/148649
ISSN
2015 Impact Factor: 3.057
2015 SCImago Journal Rankings: 1.395
PubMed Central ID
ISI Accession Number ID
Funding AgencyGrant Number
Hong Kong Research Grants CouncilHKU7798/07M
HKU 1/06C
HKU 7/CRG/09
Outstanding Young Researcher Award
Funding Information:

This work was supported by the Hong Kong Research Grants Council (HKU7798/07M), Hong Kong Research Grants Council Collaborative Research Fund (HKU 1/06C and HKU 7/CRG/09) and Outstanding Young Researcher Award (to J.W.P. Yam). I.O.L. Ng is Loke Yew Professor in Pathology. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

References
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DC FieldValueLanguage
dc.contributor.authorChan, LKen_US
dc.contributor.authorKo, FCFen_US
dc.contributor.authorSze, KMFen_US
dc.contributor.authorNg, IOLen_US
dc.contributor.authorYam, JWPen_US
dc.date.accessioned2012-05-29T06:14:22Z-
dc.date.available2012-05-29T06:14:22Z-
dc.date.issued2011en_US
dc.identifier.citationPLoS One, 2011, v. 6 n. 9, article no. e25547en_US
dc.identifier.issn1932-6203en_US
dc.identifier.urihttp://hdl.handle.net/10722/148649-
dc.description.abstractBACKGROUND: Deleted in liver cancer 1 (DLC1) serves as an important RhoGTPase activating protein (RhoGAP) protein that terminates active RhoA signaling in human cancers. Increasing evidence has demonstrated that the tumor suppressive activity of DLC1 depends not only on RhoGAP activity, but also relies on proper focal adhesion localization through its interaction with tensin family proteins. Recently, there are reports showing that DLC1 can also be found in the nucleus; however, the existence and the relative tumor suppressive activity of nuclear DLC1 have never been clearly addressed. METHODOLOGY AND PRINCIPAL FINDINGS: We herein provide new evidence that DLC1 protein, which predominantly associated with focal adhesions and localized in cytosol, dynamically shuttled between cytoplasm and nucleus. Treatment of cells with nuclear export blocker, Leptomycin B (LMB), retained DLC1 in the nucleus. To understand the nuclear entry of DLC1, we identified amino acids 600-700 of DLC1 as a novel region that is important for its nuclear localization. The tumor suppressive activity of nuclear DLC1 was directly assessed by employing a nuclear localization signal (NLS) fusion variant of DLC1 (NLS-DLC1) with preferential nuclear localization. In SMMC-7721 HCC cells, expression of NLS-DLC1 failed to suppress colony formation and actin stress fiber formation in vitro. The abrogated tumor suppressive activity of nuclear DLC1 was demonstrated for the first time in vivo by subcutaneously injecting p53(-/-) RasV12 hepatoblasts with stable NLS-DLC1 expression in nude mice. The injected hepatoblasts with NLS-DLC1 expression effectively formed tumors when compared with the non-nuclear targeted DLC1. CONCLUSIONS/SIGNIFICANCE: Our study identified a novel region responsible for the nuclear entry of DLC1 and demonstrated the functional difference of DLC1 in different cellular compartments both in vitro and in vivo.en_US
dc.languageengen_US
dc.publisherPublic Library of Science. The Journal's web site is located at http://www.plosone.org/home.actionen_US
dc.relation.ispartofPLoS Oneen_US
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.subject.meshCell Line, Tumor-
dc.subject.meshCell Nucleus - drug effects - metabolism-
dc.subject.meshFatty Acids, Unsaturated - pharmacology-
dc.subject.meshGTPase-Activating Proteins - genetics - metabolism-
dc.subject.meshTumor Suppressor Proteins - genetics - metabolism-
dc.titleNuclear-targeted deleted in liver cancer 1 (DLC1) is less efficient in exerting its tumor suppressive activity both in vitro and in vivoen_US
dc.typeArticleen_US
dc.identifier.emailChan, LK: lkchan1@hku.hken_US
dc.identifier.emailKo, FCF: bokcf@hku.hken_US
dc.identifier.emailSze, KMF: karensze@hkucc.hku.hk-
dc.identifier.emailNg, IOL: iolng@hku.hk-
dc.identifier.emailYam, JWP: judyyam@pathology.hku.hk-
dc.identifier.authorityNg, IOL=rp00335en_US
dc.identifier.authorityYam, JWP=rp00468en_US
dc.description.naturepublished_or_final_versionen_US
dc.identifier.doi10.1371/journal.pone.0025547en_US
dc.identifier.pmid21966542-
dc.identifier.pmcidPMC3180446-
dc.identifier.scopuseid_2-s2.0-80053161961en_US
dc.identifier.hkuros201435-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-80053161961&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume6en_US
dc.identifier.issue9, article no. e25547en_US
dc.identifier.isiWOS:000295932100050-
dc.publisher.placeUnited Statesen_US
dc.relation.projectMolecular pathology of liver cancer - a multidisciplinary study-

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