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DLC-1 suppresses non-small cell lung cancer growth and invasion by RhoGAP-dependent and independent mechanisms
DC Field | Value | Language |
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dc.contributor.author | Healy, Kevin D | - |
dc.contributor.author | Hodgson, Louis | - |
dc.contributor.author | Kim, Tai-Young | - |
dc.contributor.author | Shutes, Adam | - |
dc.contributor.author | Maddileti, Savitri | - |
dc.contributor.author | Juliano, Rudolph L | - |
dc.contributor.author | Hahn, Klaus M | - |
dc.contributor.author | Harden, T Kendall | - |
dc.contributor.author | Bang, Yung-Jue | - |
dc.contributor.author | Der, Channing J | - |
dc.date.accessioned | 2009-12-31T01:09:44Z | - |
dc.date.available | 2009-12-31T01:09:44Z | - |
dc.date.issued | 2007-10-13 | - |
dc.identifier.citation | Mol Carcinog. 2008 May;47(5):326-37. | en |
dc.identifier.issn | 1098-2744 (Electronic) | - |
dc.identifier.uri | http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17932950 | - |
dc.identifier.uri | https://hdl.handle.net/10371/23850 | - |
dc.description.abstract | Expression 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 anti-tumor 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-delta1. 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. | en |
dc.language.iso | en | en |
dc.publisher | Wiley-Blackwell | en |
dc.subject | Carcinoma, Non-Small-Cell Lung/metabolism/pathology/*prevention & control | en |
dc.subject | Cell Movement | en |
dc.subject | Collagen/metabolism | en |
dc.subject | DNA Primers | en |
dc.subject | Drug Combinations | en |
dc.subject | Gene Expression Regulation, Neoplastic | en |
dc.subject | Genes, Tumor Suppressor/physiology | en |
dc.subject | Guanosine Triphosphate/metabolism | en |
dc.subject | Humans | en |
dc.subject | Hydrolysis | en |
dc.subject | Laminin/metabolism | en |
dc.subject | Lung Neoplasms/metabolism/pathology/*prevention & control | en |
dc.subject | Neoplasm Invasiveness | en |
dc.subject | Phospholipase C delta/metabolism | en |
dc.subject | Polymerase Chain Reaction | en |
dc.subject | Proteoglycans/metabolism | en |
dc.subject | Tumor Cells, Cultured | en |
dc.subject | Tumor Stem Cell Assay | en |
dc.subject | Tumor Suppressor Proteins/*physiology | en |
dc.subject | rho GTP-Binding Proteins/genetics/*metabolism | en |
dc.subject | rhoA GTP-Binding Protein/genetics/*metabolism | en |
dc.subject | rhoB GTP-Binding Protein/genetics/*metabolism | en |
dc.title | DLC-1 suppresses non-small cell lung cancer growth and invasion by RhoGAP-dependent and independent mechanisms | en |
dc.type | Article | en |
dc.contributor.AlternativeAuthor | 김태영 | - |
dc.contributor.AlternativeAuthor | 방영주 | - |
dc.identifier.doi | 10.1002/mc.20389 | - |
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