Document Detail


p66(Shc) restrains Ras hyperactivation and suppresses metastatic behavior.
MedLine Citation:
PMID:  20676142     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Normal tissue cells survive and proliferate only while anchored to solid substrate. Conversely, transformed cells both survive and proliferate following detachment, having lost attachment context through unclear mechanisms. p66(Shc) is a focal adhesion-associated protein that reports cell attachment through a RhoA-dependent mechanosensory test. We find that human small cell lung cancer (SCLC) cells and mouse Lewis lung carcinoma (LLC), which display aggressive metastatic behavior, lack both p66(Shc) and retinoblastoma (pRB) and bypass anoikis. Re-expression of p66(Shc) in these cells restores anoikis and provides striking protection from metastasis by LLC cells in vivo. Notably, knockdown of p66(Shc) in normal epithelial cells leads to unrestrained Ras activation, preventing anoikis through downstream suppression of RhoA but blocking proliferation in a pRB-dependent manner, thus mimicking oncogenic Ras. Conversely, LLC and SCLC cells display constitutive Ras activation necessary to bypass anoikis, which is reversed by re-expression of p66(Shc). p66(Shc) therefore coordinates Ras-dependent control of proliferation and anchorage sensation, which can be defeated in the evolution of highly metastatic tumors by combined loss of both p66(Shc) and pRB.
Authors:
Z Ma; Z Liu; R-F Wu; L S Terada
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2010-08-02
Journal Detail:
Title:  Oncogene     Volume:  29     ISSN:  1476-5594     ISO Abbreviation:  Oncogene     Publication Date:  2010 Oct 
Date Detail:
Created Date:  2010-10-14     Completed Date:  2010-11-16     Revised Date:  2014-09-18    
Medline Journal Info:
Nlm Unique ID:  8711562     Medline TA:  Oncogene     Country:  England    
Other Details:
Languages:  eng     Pagination:  5559-67     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Anoikis*
Carcinoma, Lewis Lung / genetics,  metabolism*,  pathology
Cell Line, Tumor
Cell Proliferation
Female
Focal Adhesions
Humans
Immunoblotting
Lung Neoplasms / genetics,  metabolism,  pathology
Mice
Mice, Inbred C57BL
Neoplasm Metastasis
RNA Interference
Retinoblastoma Protein / genetics,  metabolism
Shc Signaling Adaptor Proteins / genetics,  metabolism*
Small Cell Lung Carcinoma / genetics,  metabolism,  pathology
ras Proteins / genetics,  metabolism*
rhoA GTP-Binding Protein / genetics,  metabolism
Grant Support
ID/Acronym/Agency:
R01 HL067256/HL/NHLBI NIH HHS; R01 HL067256-09/HL/NHLBI NIH HHS; R01-HL061897/HL/NHLBI NIH HHS; R01-HL067256/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Retinoblastoma Protein; 0/SHC1 protein, human; 0/Shc Signaling Adaptor Proteins; 0/Shc1 protein, mouse; EC 3.6.5.2/ras Proteins; EC 3.6.5.2/rhoA GTP-Binding Protein
Comments/Corrections
Comment In:
Oncogene. 2010 Oct 14;29(41):5556-8   [PMID:  20711240 ]

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