Document Detail

Involvement of Lgl and Mahjong/VprBP in cell competition.
MedLine Citation:
PMID:  20644714     Owner:  NLM     Status:  MEDLINE    
During the initial stages of carcinogenesis, transformation events occur in a single cell within an epithelial monolayer. However, it remains unknown what happens at the interface between normal and transformed epithelial cells during this process. In Drosophila, it has been recently shown that normal and transformed cells compete with each other for survival in an epithelial tissue; however the molecular mechanisms whereby "loser cells" undergo apoptosis are not clearly understood. Lgl (lethal giant larvae) is a tumor suppressor protein and plays a crucial role in oncogenesis in flies and mammals. Here we have examined the involvement of Lgl in cell competition and shown that a novel Lgl-binding protein is involved in Lgl-mediated cell competition. Using biochemical immunoprecipitation methods, we first identified Mahjong as a novel binding partner of Lgl in both flies and mammals. In Drosophila, Mahjong is an essential gene, but zygotic mahjong mutants (mahj(-/-)) do not have obvious patterning defects during embryonic or larval development. However, mahj(-/-) cells undergo apoptosis when surrounded by wild-type cells in the wing disc epithelium. Importantly, comparable phenomena also occur in Mahjong-knockdown mammalian cells; Mahjong-knockdown Madin-Darby canine kidney epithelial cells undergo apoptosis, only when surrounded by non-transformed cells. Similarly, apoptosis of lgl(-/-) cells is induced when they are surrounded by wild-type cells in Drosophila wing discs. Phosphorylation of the c-Jun N-terminal kinase (JNK) is increased in mahj(-/-) or lgl(-/-) mutant cells, and expression of Puckered (Puc), an inhibitor of the JNK pathway, suppresses apoptosis of these mutant cells surrounded by wild-type cells, suggesting that the JNK pathway is involved in mahj- or lgl-mediated cell competition. Finally, we have shown that overexpression of Mahj in lgl(-/-) cells strongly suppresses JNK activation and blocks apoptosis of lgl(-/-) cells in the wild-type wing disc epithelium. These data indicate that Mahjong interacts with Lgl biochemically and genetically and that Mahjong and Lgl function in the same pathway to regulate cellular competitiveness. As far as we are aware, this is the first report that cell competition can occur in a mammalian cell culture system.
Yoichiro Tamori; Carl Uli Bialucha; Ai-Guo Tian; Mihoko Kajita; Yi-Chun Huang; Mark Norman; Nicholas Harrison; John Poulton; Kenzo Ivanovitch; Lena Disch; Tao Liu; Wu-Min Deng; Yasuyuki Fujita
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-07-13
Journal Detail:
Title:  PLoS biology     Volume:  8     ISSN:  1545-7885     ISO Abbreviation:  PLoS Biol.     Publication Date:  2010  
Date Detail:
Created Date:  2010-07-20     Completed Date:  2010-10-26     Revised Date:  2014-02-19    
Medline Journal Info:
Nlm Unique ID:  101183755     Medline TA:  PLoS Biol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  e1000422     Citation Subset:  IM    
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MeSH Terms
Carrier Proteins / metabolism*
Cell Line
Clone Cells
Drosophila Proteins / metabolism*
Drosophila melanogaster / cytology*,  metabolism*
Epithelial Cells / cytology,  metabolism
Epithelium / metabolism
Gene Knockdown Techniques
JNK Mitogen-Activated Protein Kinases / metabolism
Protein Binding
Tumor Suppressor Proteins / metabolism*
Wing / cytology,  metabolism
Grant Support
1R01GM072562/GM/NIGMS NIH HHS; MC_U122669938//Medical Research Council; //Medical Research Council
Reg. No./Substance:
0/Carrier Proteins; 0/Drosophila Proteins; 0/Tumor Suppressor Proteins; 0/VprBP protein, human; 0/lethal (2) giant larvae protein, Drosophila; 0/mahjong protein, Drosophila; EC Mitogen-Activated Protein Kinases
Comment In:
Nat Rev Cancer. 2010 Sep;10(9):598   [PMID:  20803809 ]
PLoS Biol. 2010;8(7):e1000423   [PMID:  20644641 ]

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