Document Detail

Telomerase induces immortalization of human esophageal keratinocytes without p16INK4a inactivation.
MedLine Citation:
PMID:  12939398     Owner:  NLM     Status:  MEDLINE    
Normal human somatic cells have a finite life span and undergo replicative senescence after a limited number of cell divisions. Erosion of telomeric DNA has emerged as a key factor in senescence, which is antagonized during cell immortalization and transformation. To clarify the involvement of telomerase in the immortalization of keratinocytes, catalytic subunit of telomerase (hTERT) expression was restored in normal human esophageal epithelial cells (EPC2). EPC2-hTERT cells overcame senescence and were immortalized without p16INK4a genetic or epigenetic alterations. p16INK4a was expressed at moderate levels and remained functional as evidenced by induction with UV treatment and binding to cyclin-dependent kinase 4 and 6. There were no mutations in the p53 gene, and p53 was functionally intact. Importantly, senescence could be activated in the immortalized EPC2-hTERT cells by overexpression of oncogenic H-ras or p16INK4a. Furthermore, the EPC2-hTERT cells yielded basal cell hyperplasia in an innovative organotypic culture system in contrast to a normal epithelium from parental cells. These comprehensive results indicate that the expression of telomerase induces immortalization of normal human esophageal keratinocytes without inactivation of p16INK4a/pRb pathway or abrogation of the p53 pathway.
Hideki Harada; Hiroshi Nakagawa; Kenji Oyama; Munenori Takaoka; Claudia D Andl; Birgit Jacobmeier; Alexander von Werder; Gregory H Enders; Oliver G Opitz; Anil K Rustgi
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Molecular cancer research : MCR     Volume:  1     ISSN:  1541-7786     ISO Abbreviation:  Mol. Cancer Res.     Publication Date:  2003 Aug 
Date Detail:
Created Date:  2003-08-26     Completed Date:  2004-04-02     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  101150042     Medline TA:  Mol Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  729-38     Citation Subset:  IM    
Gastroenterology Division, University of Pennsylvania, Philadelphia, PA 19104, USA.
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MeSH Terms
Cell Aging*
Cell Differentiation
Cell Division
Cell Transformation, Neoplastic
Cells, Cultured
Cyclin-Dependent Kinase Inhibitor p16 / genetics,  metabolism*
Cyclins / genetics,  metabolism
DNA-Binding Proteins
Epithelial Cells / cytology,  metabolism
Esophagus / cytology
Gene Expression
Genes, p16
Genes, p53
Genes, ras
Keratinocytes / cytology*,  metabolism*
Telomerase / genetics,  metabolism*
Grant Support
Reg. No./Substance:
0/Cyclin-Dependent Kinase Inhibitor p16; 0/Cyclins; 0/DNA-Binding Proteins; EC

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