| Immortalization eliminates a roadblock during cellular reprogramming into iPS cells. | |
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MedLine Citation:
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PMID: 19668190 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The overexpression of defined transcription factors in somatic cells results in their reprogramming into induced pluripotent stem (iPS) cells. The extremely low efficiency and slow kinetics of in vitro reprogramming suggest that further rare events are required to generate iPS cells. The nature and identity of these events, however, remain elusive. We noticed that the reprogramming potential of primary murine fibroblasts into iPS cells decreases after serial passaging and the concomitant onset of senescence. Consistent with the notion that loss of replicative potential provides a barrier for reprogramming, here we show that cells with low endogenous p19(Arf) (encoded by the Ink4a/Arf locus, also known as Cdkn2a locus) protein levels and immortal fibroblasts deficient in components of the Arf-Trp53 pathway yield iPS cell colonies with up to threefold faster kinetics and at a significantly higher efficiency than wild-type cells, endowing almost every somatic cell with the potential to form iPS cells. Notably, the acute genetic ablation of Trp53 (also known as p53) in cellular subpopulations that normally fail to reprogram rescues their ability to produce iPS cells. Our results show that the acquisition of immortality is a crucial and rate-limiting step towards the establishment of a pluripotent state in somatic cells and underscore the similarities between induced pluripotency and tumorigenesis. |
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Authors:
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Jochen Utikal; Jose M Polo; Matthias Stadtfeld; Nimet Maherali; Warakorn Kulalert; Ryan M Walsh; Adam Khalil; James G Rheinwald; Konrad Hochedlinger |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2009-08-09 |
Journal Detail:
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Title: Nature Volume: 460 ISSN: 1476-4687 ISO Abbreviation: Nature Publication Date: 2009 Aug |
Date Detail:
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Created Date: 2009-08-28 Completed Date: 2009-09-28 Revised Date: - |
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: 1145-8 Citation Subset: IM |
Affiliation:
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Massachusetts General Hospital Cancer Center and Center for Regenerative Medicine, Harvard Stem Cell Institute, 185 Cambridge Street, Boston, Massachusetts 02114, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Cell Aging / physiology* Cell Differentiation Cell Division Cell Line Cells, Cultured Cyclin-Dependent Kinase Inhibitor p16 / deficiency, genetics, metabolism Down-Regulation Fibroblasts / cytology, metabolism Gene Expression Humans Keratinocytes Kinetics Mice Mice, SCID Nuclear Reprogramming / physiology* Pluripotent Stem Cells / cytology*, metabolism Tumor Suppressor Protein p53 / deficiency, genetics, metabolism |
| Chemical | |
Reg. No./Substance:
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0/Cdkn2a protein, mouse; 0/Cyclin-Dependent Kinase Inhibitor p16; 0/Tumor Suppressor Protein p53 |
| Comments/Corrections | |
Comment In:
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Nature. 2009 Aug 27;460(7259):1085-6
[PMID:
19713919
]
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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