Document Detail

Novel roles of hakai in cell proliferation and oncogenesis.
MedLine Citation:
PMID:  19535458     Owner:  NLM     Status:  MEDLINE    
During tumor development, cells acquire multiple phenotypic changes upon misregulation of oncoproteins and tumor suppressor proteins. Hakai was originally identified as an E3 ubiquitin-ligase for the E-cadherin complex that regulates cell-cell contacts. Here, we present evidence that Hakai plays a crucial role in various cellular processes and tumorigenesis. Overexpression of Hakai affects not only cell-cell contacts but also proliferation in both epithelial and fibroblast cells. Furthermore, the knockdown of Hakai significantly suppresses proliferation of transformed epithelial cells. Expression of Hakai is correlated to the proliferation rate in human tissues and is highly up-regulated in human colon and gastric adenocarcinomas. Moreover, we identify PTB-associated splicing factor (PSF), an RNA-binding protein, as a novel Hakai-interacting protein. By using cDNA arrays, we have determined various specific PSF-associated mRNAs encoding proteins that are involved in several cancer-related processes. Hakai affects the ability of PSF to bind these mRNAs, and expression of PSF short hairpin RNA or a dominant-negative PSF mutant significantly suppresses proliferation of Hakai-overexpressing cells. Collectively, these results suggest that Hakai is an important regulator of cell proliferation and that Hakai may be an oncoprotein and a potential molecular target for cancer treatment.
Angélica Figueroa; Hirokazu Kotani; Yoshinobu Toda; Krystyna Mazan-Mamczarz; Eva-Christina Mueller; Albrecht Otto; Lena Disch; Mark Norman; Rasika Mohan Ramdasi; Mohammed Keshtgar; Myriam Gorospe; Yasuyuki Fujita
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-06-17
Journal Detail:
Title:  Molecular biology of the cell     Volume:  20     ISSN:  1939-4586     ISO Abbreviation:  Mol. Biol. Cell     Publication Date:  2009 Aug 
Date Detail:
Created Date:  2009-08-03     Completed Date:  2010-02-17     Revised Date:  2014-02-19    
Medline Journal Info:
Nlm Unique ID:  9201390     Medline TA:  Mol Biol Cell     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3533-42     Citation Subset:  IM    
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MeSH Terms
Blotting, Western
Cadherins / genetics,  metabolism
Cell Adhesion
Cell Line
Cell Line, Tumor
Cell Proliferation*
Endometrium / metabolism*
Flow Cytometry
Fluorescent Antibody Technique
Lymph Nodes / metabolism*
NIH 3T3 Cells
Neoplasms / genetics,  metabolism,  pathology
Oligonucleotide Array Sequence Analysis
Protein Binding
RNA Interference
RNA, Messenger / genetics,  metabolism
RNA-Binding Proteins / genetics,  metabolism
Ubiquitin-Protein Ligases / genetics,  metabolism*
Grant Support
MC_U122669938//Medical Research Council; //Medical Research Council
Reg. No./Substance:
0/Cadherins; 0/PTB-associated splicing factor; 0/RNA, Messenger; 0/RNA-Binding Proteins; EC protein, human; EC Ligases

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