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DLC-1 suppresses non-small cell lung cancer growth and invasion by RhoGAP-dependent and independent mechanisms

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dc.contributor.authorHealy, Kevin D.-
dc.contributor.authorHodgson, Louis-
dc.contributor.authorKim, Tai-Young-
dc.contributor.authorShutes, Adam-
dc.contributor.authorMaddileti, Savitri-
dc.contributor.authorJuliano, Rudolph L.-
dc.contributor.authorHahn, Klaus M.-
dc.contributor.authorHarden, T. Kendall-
dc.contributor.authorBang, Yung-Jue-
dc.contributor.authorDer, Channing J.-
dc.date.accessioned2010-07-04T23:19:32Z-
dc.date.available2010-07-04T23:19:32Z-
dc.date.issued2008-05-
dc.identifier.citationMolecular Carcinogenesis, Vol.47 No.5, pp.326-337-
dc.identifier.issn0899-1987-
dc.identifier.other119476-
dc.identifier.urihttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17932950-
dc.identifier.urihttps://hdl.handle.net/10371/68196-
dc.description.abstractExpression of the tumor suppressor deleted in liver cancer-1 (DLC-1) is lost in non-small cell lung (NSCLC) and other human carcinomas, and ectopic DLC-1 expression dramatically reduces proliferation and tumorigenicity. DLC-1 is a multi-domain protein that includes a Rho GTPase activating protein (RhoGAP) domain which has been hypothesized to be the basis of its tumor suppressive actions. To address the importance of the RhoGAP function of DLC-1 in tumor suppression, we performed biochemical and biological studies evaluating DLC-1 in NSCLC. Full-length DLC-1 exhibited strong GAP activity for RhoA as well as RhoB and RhoC, but only very limited activity for Cdc42 in vitro. In contrast, the isolated RhoGAP domain showed 5- to 20-fold enhanced activity for RhoA, RhoB, RhoC, and Cdc42. DLC-1 protein expression was absent in six of nine NSCLC cell lines. Restoration of DLC-1 expression in DLC-1-deficient NSCLC cell lines reduced RhoA activity, and experiments with a RhoA biosensor demonstrated that DLC-1 dramatically reduces RhoA activity at the leading edge of cellular protrusions. Furthermore, DLC-1 expression in NSCLC cell lines impaired both anchorage-dependent and -independent growth, as well as invasion in vitro. Surprisingly, we found that the antitumor activity of DLC-1 was due to both RhoGAP-dependent and -independent activities. Unlike the rat homologue p122RhoGAP, DLC-1 was not capable of activating the phospholipid hydrolysis activity of phospholipase C-delta 1. Combined, these studies provide information on the mechanism of DLC-1 function and regulation, and further support the role of DLC-1 tumor suppression in NSCLC. (c) 2007 Wiley-Liss, Inc.-
dc.description.sponsorshipsupported by grants
from the National Institutes of Health to R.L.J.
(PO1HL4500), to K.M.H. (GM64346 and GM57464),
to T.K.H. (GM57391) and to C.J.D. (CA063071 and
CA67771). K.D.H. was supported by a fellowship
from the American Cancer Society and A.S. by a
fellowship from the Susan G. Komen Breast Cancer
Foundation.
en
dc.language.isoenen
dc.publisherWiley-Blackwellen
dc.subjectGTPase activating protein-
dc.subjectRho GTPases-
dc.subjecttumor suppressor-
dc.titleDLC-1 suppresses non-small cell lung cancer growth and invasion by RhoGAP-dependent and independent mechanisms-
dc.typeArticle-
dc.contributor.AlternativeAuthor방영주-
dc.identifier.doi10.1002/mc.20389-
dc.citation.journaltitleMolecular Carcinogenesis-
dc.identifier.scopusid2-s2.0-42949100728-
dc.citation.endpage337-
dc.citation.number5-
dc.citation.startpage326-
dc.citation.volume47-
dc.identifier.urlhttps://onlinelibrary.wiley.com/doi/full/10.1002/mc.20389-
dc.identifier.rimsid119476-
dc.identifier.sci000255483200002-
dc.contributor.affiliatedAuthorBang, Yung-Jue-
Appears in Collections:
College of Medicine/School of Medicine (의과대학/대학원)Internal Medicine (내과학전공)Journal Papers (저널논문_내과학전공)
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