Document Detail


Efficient immortalization of primary human cells by p16INK4a-specific short hairpin RNA or Bmi-1, combined with introduction of hTERT.
MedLine Citation:
PMID:  17233832     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Activation of telomerase is sufficient for immortalization of some types of human cells but additional factors may also be essential. It has been proposed that stress imposed by inadequate culture conditions induces senescence due to accumulation of p16(INK4a). Here, we present evidence that many human cell types undergo senescence by activation of the p16(INK4a)/Rb pathway, and that introduction of Bmi-1 can inhibit p16(INK4a) expression and extend the life span of human epithelial cells derived from skin, mammary gland and lung. Introduction of p16(INK4a)-specific short hairpin RNA, as well as Bmi-1, suppressed p16(INK4a) expression in human mammary epithelial cells without promoter methylation, and extended their life span. Subsequent introduction of hTERT, the telomerase catalytic subunit, into cells with low p16(INK4a) levels resulted in efficient immortalization of three cell types without crisis or growth arrest. The majority of the human mammary epithelial cells thus immortalized showed almost normal ploidy as judged by G-banding and spectral karyotyping analysis. Our data suggest that inhibition of p16(INK4a) and introduction of hTERT can immortalize many human cell types with little chromosomal instability.
Authors:
Kei Haga; Shin-ichi Ohno; Takashi Yugawa; Mako Narisawa-Saito; Masatoshi Fujita; Michiie Sakamoto; Denise A Galloway; Tohru Kiyono
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Cancer science     Volume:  98     ISSN:  1347-9032     ISO Abbreviation:  Cancer Sci.     Publication Date:  2007 Feb 
Date Detail:
Created Date:  2007-01-19     Completed Date:  2007-02-23     Revised Date:  2008-11-21    
Medline Journal Info:
Nlm Unique ID:  101168776     Medline TA:  Cancer Sci     Country:  England    
Other Details:
Languages:  eng     Pagination:  147-54     Citation Subset:  IM    
Affiliation:
Virology Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuoku 104-0045, Tokyo, Japan.
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MeSH Terms
Descriptor/Qualifier:
Catalysis
Cell Aging
Cell Proliferation
Cells, Cultured
Cyclin-Dependent Kinase Inhibitor p16 / genetics*,  metabolism*
DNA Methylation
Down-Regulation
Enzyme Activation
Epithelial Cells / cytology,  metabolism
Humans
Karyotyping
Keratinocytes / metabolism
Nuclear Proteins / genetics*,  metabolism*
Promoter Regions, Genetic / genetics
Proto-Oncogene Proteins / genetics*,  metabolism*
RNA Interference
Repressor Proteins / genetics*,  metabolism*
Telomerase / genetics,  metabolism*
Up-Regulation
Chemical
Reg. No./Substance:
0/Cyclin-Dependent Kinase Inhibitor p16; 0/Nuclear Proteins; 0/Proto-Oncogene Proteins; 0/Repressor Proteins; 138791-04-5/BMI1 protein, human; EC 2.7.7.49/Telomerase

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