Document Detail


A novel senescence-evasion mechanism involving Grap2 and Cyclin D interacting protein inactivation by Ras associated with diabetes in cancer cells under doxorubicin treatment.
MedLine Citation:
PMID:  20460530     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Ras associated with diabetes (Rad) is a Ras-related GTPase that promotes cell growth by accelerating cell cycle transitions. Rad knockdown induced cell cycle arrest and premature senescence without additional cellular stress in multiple cancer cell lines, indicating that Rad expression might be critical for the cell cycle in these cells. To investigate the precise function of Rad in this process, we used human Rad as bait in a yeast two-hybrid screening system and sought Rad-interacting proteins. We identified the Grap2 and cyclin D interacting protein (GCIP)/DIP1/CCNDBP1/HHM, a cell cycle-inhibitory molecule, as a binding partner of Rad. Further analyses revealed that Rad binds directly to GCIP in vitro and coimmunoprecipitates with GCIP from cell lysates. Rad translocates GCIP from the nucleus to the cytoplasm, thereby inhibiting the tumor suppressor activity of GCIP, which occurs in the nucleus. Furthermore, in the presence of Rad, GCIP loses its ability to reduce retinoblastoma phosphorylation and inhibit cyclin D1 activity. The function of Rad in transformation is also evidenced by increased telomerase activity and colony formation according to Rad expression level. In vivo tumorigenesis analyses revealed that tumors derived from Rad knockdown cells were significantly smaller than those from control cells (P = 0.0131) and the preestablished tumors are reduced in size after the injection of siRad (P = 0.0064). Therefore, we propose for the first time that Rad may promote carcinogenesis at least in part by inhibiting GCIP-mediated tumor suppression.
Authors:
Inkyoung Lee; Seon-Yong Yeom; Sook-Ja Lee; Won Ki Kang; Chaehwa Park
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-05-11
Journal Detail:
Title:  Cancer research     Volume:  70     ISSN:  1538-7445     ISO Abbreviation:  Cancer Res.     Publication Date:  2010 Jun 
Date Detail:
Created Date:  2010-06-02     Completed Date:  2010-06-17     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  2984705R     Medline TA:  Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4357-65     Citation Subset:  IM    
Copyright Information:
Copyright 2010 AACR.
Affiliation:
Biomedical Research Institute, Samsung Medical Center and Department of Medicine, Sungkyunkwan University School of Medicine, Seoul, Korea.
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MeSH Terms
Descriptor/Qualifier:
Animals
Cell Aging / drug effects,  physiology
Cell Line, Tumor
Cyclin D / metabolism
Cyclin-Dependent Kinase Inhibitor p27 / metabolism
Doxorubicin / pharmacology*
Drug Resistance, Neoplasm
Female
Hela Cells
Humans
Male
Mice
Mice, Nude
Neoplasms / drug therapy,  metabolism,  pathology*
Phosphorylation
Retinoblastoma Protein / metabolism
Telomerase / metabolism
Transcription Factors / biosynthesis,  genetics,  physiology*
ras Proteins / biosynthesis,  genetics,  physiology*
Chemical
Reg. No./Substance:
0/CCNDBP1 protein, human; 0/Cyclin D; 0/RRAD protein, human; 0/Retinoblastoma Protein; 0/Transcription Factors; 147604-94-2/Cyclin-Dependent Kinase Inhibitor p27; 23214-92-8/Doxorubicin; EC 2.7.7.49/Telomerase; EC 3.6.5.2/ras Proteins

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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