Document Detail

p53 pathway in renal cell carcinoma is repressed by a dominant mechanism.
MedLine Citation:
PMID:  15026329     Owner:  NLM     Status:  MEDLINE    
Renal cell carcinoma (RCC) rarely acquires mutations in p53 tumor suppressor gene, suggesting that p53 signaling in this tumor type might be repressed by some other mechanism. In fact, all four RCC-derived cell lines we tested maintained wild-type p53 but were not capable of transactivating p53-responsive reporters and endogenous p53-responsive genes. p53 protein in RCC showed normal response to genotoxic stress, including accumulation, nuclear translocation, and activation of specific DNA binding. Functional and expression analysis of Mdm2, MdmX, and Arf showed lack of involvement of these p53 regulators in the observed defect of p53 function in RCC. However, activation of p53-mediated transactivation could be achieved by extremely high levels of p53 attained by lentivirus vector-driven transduction, suggesting the involvement of a dominant inhibitor in repression of p53-dependent transactivation in RCC. Consistently, p53 inactivation prevailed in the hybrids of RCC cells with the cells possessing fully functional p53. Remarkably, cells of normal kidney epithelium also caused partial p53 repression in cell fusion experiments, suggesting that RCC-specific p53 repression may be based on an unknown dominant mechanism also acting in normal kidney tissue.
Katerina V Gurova; Jason E Hill; Olga V Razorenova; Peter M Chumakov; Andrei V Gudkov
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Cancer research     Volume:  64     ISSN:  0008-5472     ISO Abbreviation:  Cancer Res.     Publication Date:  2004 Mar 
Date Detail:
Created Date:  2004-03-17     Completed Date:  2004-04-08     Revised Date:  2008-11-21    
Medline Journal Info:
Nlm Unique ID:  2984705R     Medline TA:  Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1951-8     Citation Subset:  IM    
Department of Molecular Biology, Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
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MeSH Terms
Carcinoma, Renal Cell / genetics,  metabolism*
Cell Fusion
Cell Nucleus / metabolism
DNA Damage
Electrophoretic Mobility Shift Assay
Gene Expression Regulation, Neoplastic
Genes, Dominant*
Hybrid Cells
Kidney / metabolism
Kidney Neoplasms / genetics,  metabolism*
Lentivirus / genetics
Nuclear Proteins*
Promoter Regions, Genetic
Protein Transport
Proto-Oncogene Proteins / metabolism
Proto-Oncogene Proteins c-mdm2
Retroviridae / genetics
Signal Transduction*
Transcriptional Activation
Tumor Suppressor Protein p14ARF / metabolism
Tumor Suppressor Protein p53 / deficiency,  genetics,  metabolism*
Grant Support
Reg. No./Substance:
0/Nuclear Proteins; 0/Proto-Oncogene Proteins; 0/Tumor Suppressor Protein p14ARF; 0/Tumor Suppressor Protein p53; EC 1.13.12.-/Luciferases; EC protein, human; EC Proteins c-mdm2

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