Document Detail


Deleted in liver cancer 2 suppresses cell growth via the regulation of the Raf-1-ERK1/2-p70S6K signalling pathway.
MedLine Citation:
PMID:  20629949     Owner:  NLM     Status:  In-Process    
Abstract/OtherAbstract:
BACKGROUND: Deleted in liver cancer 2 (DLC2) gene, a putative tumour suppressor gene, encodes a Rho GTPase-activating protein (RhoGAP) with GAP activity specific for RhoA. It exhibits tumour suppressor functions and inhibits tumour cell proliferation, migration as well as transformation.
AIMS: In this study, we aimed to investigate the underlying mechanisms of the DLC2 gene in suppressing cell migration and cell growth. HepG2 hepatoma cells were stably transfected with the DLC2γ isoform, which contains the RhoGAP domain.
METHODS AND RESULTS: On performing immunofluorescence staining and Western blot analysis, the expression of the focal adhesion protein paxillin was found to be much reduced in DLC2γ-stable clones. Upon flow cytometric analysis of the cell cycle profiles, the DLC2γ-stable clones were shown to have a higher population of cells arrested at the G1 phase than the EGFP vector-stable clone, suggesting that downregulation of RhoA activity in DLC2γ-stable clones inhibited cell cycle progression. In the DLC2γ-stable clone, the levels of Raf-1 and extracellular signal-regulated kinase (ERK) 1/2 were decreased as compared with those of the parental HepG2, EGFP vector and DLC2γ-GAP defective mutant-stable clones. Furthermore, the ribosomal kinase p70S6K, a downstream target of ERK1/2, was suppressed in the DLC2-stable clones. On the contrary, when DLC2 was knocked down by siRNA in HepG2 cells, the expression levels of phospho-p70S6K and phospho-ERK1/2 were upregulated.
CONCLUSION: Our data show that DLC2 inhibits the activity of Raf-1-ERK1/2-p70S6K via its RhoGAP function, resulting in the suppression of cell growth. Further studies on the molecular signalling between DLC2 and p70S6K may provide an insight into its growth suppressor function.
Authors:
Thomas Ho-Yin Leung; Judy Wai-Ping Yam; Lo Kong Chan; Yick-Pang Ching; Irene Oi-Lin Ng
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Liver international : official journal of the International Association for the Study of the Liver     Volume:  30     ISSN:  1478-3231     ISO Abbreviation:  Liver Int.     Publication Date:  2010 Oct 
Date Detail:
Created Date:  2010-11-08     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101160857     Medline TA:  Liver Int     Country:  England    
Other Details:
Languages:  eng     Pagination:  1315-23     Citation Subset:  IM    
Copyright Information:
© 2010 John Wiley & Sons A/S.
Affiliation:
Department of Pathology, The University of Hong Kong, Hong Kong, China.
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