| p66(Shc) restrains Ras hyperactivation and suppresses metastatic behavior. | |
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MedLine Citation:
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PMID: 20676142 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Z Ma; Z Liu; R-F Wu; L S Terada |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2010-08-02 |
Journal Detail:
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Title: Oncogene Volume: 29 ISSN: 1476-5594 ISO Abbreviation: Oncogene Publication Date: 2010 Oct |
Date Detail:
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Created Date: 2010-10-14 Completed Date: 2010-11-16 Revised Date: 2011-07-25 |
Medline Journal Info:
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Nlm Unique ID: 8711562 Medline TA: Oncogene Country: England |
Other Details:
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Languages: eng Pagination: 5559-67 Citation Subset: IM |
Affiliation:
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Department of Internal Medicine, Division of Pulmonary and Critical Care, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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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:
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R01 HL067256-09/HL/NHLBI NIH HHS; R01-HL061897/HL/NHLBI NIH HHS; R01-HL067256/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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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:
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Oncogene. 2010 Oct 14;29(41):5556-8
[PMID:
20711240
]
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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