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.
journal_name
Mol Carcinogjournal_title
Molecular carcinogenesisauthors
Healy KD,Hodgson L,Kim TY,Shutes A,Maddileti S,Juliano RL,Hahn KM,Harden TK,Bang YJ,Der CJdoi
10.1002/mc.20389subject
Has Abstractpub_date
2008-05-01 00:00:00pages
326-37issue
5eissn
0899-1987issn
1098-2744journal_volume
47pub_type
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pub_type: 杂志文章
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pub_type: 杂志文章
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更新日期:1996-02-01 00:00:00
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journal_title:Molecular carcinogenesis
pub_type: 杂志文章
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更新日期:1997-10-01 00:00:00
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pub_type: 杂志文章
doi:10.1002/(SICI)1098-2744(199603)15:3<176::AID-MC3>3
更新日期:1996-03-01 00:00:00
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pub_type: 杂志文章
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更新日期:2019-01-01 00:00:00
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journal_title:Molecular carcinogenesis
pub_type: 杂志文章
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更新日期:2012-08-01 00:00:00
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更新日期:2010-06-01 00:00:00
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更新日期:2005-12-01 00:00:00
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journal_title:Molecular carcinogenesis
pub_type: 杂志文章
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更新日期:2018-06-01 00:00:00
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pub_type: 杂志文章
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journal_title:Molecular carcinogenesis
pub_type: 杂志文章
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更新日期:1992-01-01 00:00:00
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