| Both Rb/p16INK4a inactivation and telomerase activity are required to immortalize human epithelial cells. | |
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MedLine Citation:
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PMID: 9817205 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Normal human cells undergo a limited number of divisions in culture and enter a non-dividing state called replicative senescence. Senescence is accompanied by several changes, including an increase in inhibitors of cyclin-dependent kinases and telomere shortening. The mechanisms by which viral oncogenes reverse these processes are not fully understood, although a general requirement for oncoproteins such as human papillomavirus E6 and E7 has suggested that the p53 and Rb pathways are targeted. Expression of the catalytic component of telomerase, hTERT, alone significantly extends the lifespan of human fibroblasts. Here we show that telomerase activity is not sufficient for immortalization of human keratinocyte or mammary epithelial cells: we find that neither addition of hTERT nor induction of telomerase activity by E6, both of which are active in maintaining telomere length, results in immortalization. Inactivation of the Rb/p16 pathway by E7 or downregulation of p16 expression, in combination with telomerase activity, however, is able to immortalize epithelial cells efficiently. Elimination of p53 and of the DNA-damage-induced G1 checkpoint is not necessary for immortalization, neither is elimination of p19ARF. |
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Authors:
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T Kiyono; S A Foster; J I Koop; J K McDougall; D A Galloway; A J Klingelhutz |
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Publication Detail:
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Type: Journal Article; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: Nature Volume: 396 ISSN: 0028-0836 ISO Abbreviation: Nature Publication Date: 1998 Nov |
Date Detail:
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Created Date: 1998-11-20 Completed Date: 1998-11-20 Revised Date: 2006-11-15 |
Medline Journal Info:
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Nlm Unique ID: 0410462 Medline TA: Nature Country: ENGLAND |
Other Details:
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Languages: eng Pagination: 84-8 Citation Subset: IM |
Affiliation:
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Cancer Biology Program, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Breast
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cytology Cell Aging / physiology* Cell Transformation, Neoplastic Cell Transformation, Viral Cells, Cultured Cyclin-Dependent Kinase Inhibitor p16 / antagonists & inhibitors, physiology* DNA-Binding Proteins Enzyme Induction Humans Keratinocytes / cytology Oncogene Proteins, Viral / physiology Proteins / physiology RNA* Repressor Proteins* Retinoblastoma Protein / antagonists & inhibitors, physiology* Telomerase / physiology* |
| Chemical | |
Reg. No./Substance:
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0/Cyclin-Dependent Kinase Inhibitor p16; 0/DNA-Binding Proteins; 0/E6 protein, Human papillomavirus type 16; 0/Oncogene Proteins, Viral; 0/Proteins; 0/Repressor Proteins; 0/Retinoblastoma Protein; 0/telomerase RNA; 63231-63-0/RNA; EC 2.7.7.49/Telomerase |
| Comments/Corrections | |
Comment In:
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Nature. 1998 Nov 5;396(6706):23-4
[PMID:
9817198
]
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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