Document Detail


Downregulation of the pro-apoptotic protein Bak is required for the ras-induced transformation of intestinal epithelial cells.
MedLine Citation:
PMID:  9843689     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Anoikis is a form of programmed cell death induced in normal epithelial cells by detachment from the extracellular matrix [1] [2] [3]. In epithelial cells of the intestine and other organs, activated rasinduces resistance to anoikis [3] [4], but the actual molecular effectors directly involved in the apoptotic machinery that execute or block anoikis have not yet been identified. Bak, a pro-apoptotic member of the Bcl-2 family, is downregulated in a high proportion of colorectal tumours [5]. In addition, Bak is an important regulator of apoptosis in normal intestinal epithelial cells [6] [7]. Here, we show that activated rasinduces the downregulation of Bak in rat and human intestinal epithelial cells. This ras-induced downregulation of Bak expression could be suppressed by an inhibitor of phosphatidylinositol (PI) 3-kinase, an enzyme already implicated in ras-induced resistance to anoikis [8]. Ectopic expression of Bak in ras-transformed rat intestinal epithelial IEC-18 cells inhibited ras-induced resistance to anoikis and significantly reduced their tumorigenicity. We conclude, therefore, that the ability of rasto downregulate Bak, and the consequent resistance to anoikis, are essential components of the transforming capacity of this oncogene in intestinal epithelial cells.
Authors:
K Rosen; J Rak; J Jin; R S Kerbel; M J Newman; J Filmus
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Current biology : CB     Volume:  8     ISSN:  0960-9822     ISO Abbreviation:  Curr. Biol.     Publication Date:  1998 Dec 
Date Detail:
Created Date:  1999-02-08     Completed Date:  1999-02-08     Revised Date:  2005-11-17    
Medline Journal Info:
Nlm Unique ID:  9107782     Medline TA:  Curr Biol     Country:  ENGLAND    
Other Details:
Languages:  eng     Pagination:  1331-4     Citation Subset:  IM    
Affiliation:
Department of Cancer Biology Research Sunnybrook Health Science Centre S-218 Research Building 2075 Bayview Avenue Toronto Ontario M4N 3M5 Canada.
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MeSH Terms
Descriptor/Qualifier:
1-Phosphatidylinositol 3-Kinase / antagonists & inhibitors
Animals
Apoptosis / genetics*,  physiology*
Cell Transformation, Neoplastic / genetics*,  metabolism*
Chromones / pharmacology
Clone Cells
Down-Regulation
Enzyme Inhibitors / pharmacology
Epithelial Cells / metabolism
Genes, ras*
Humans
Intestines / cytology*,  metabolism*
Membrane Proteins / genetics*,  physiology*
Morpholines / pharmacology
Rats
Transfection
bcl-2 Homologous Antagonist-Killer Protein
Chemical
Reg. No./Substance:
0/BAK1 protein, human; 0/Bak1 protein, rat; 0/Chromones; 0/Enzyme Inhibitors; 0/Membrane Proteins; 0/Morpholines; 0/bcl-2 Homologous Antagonist-Killer Protein; 154447-36-6/2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; EC 2.7.1.137/1-Phosphatidylinositol 3-Kinase

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