| Telomerase upregulation is a postcrisis event during senescence bypass and immortalization of two Nijmegen breakage syndrome T cell cultures. | |
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MedLine Citation:
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PMID: 20089118 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Our knowledge on immortalization and telomere biology is mainly based on genetically manipulated cells analyzed before and many population doublings post growth crisis. The general view is that growth crisis is telomere length (TL) dependent and that escape from crisis is coupled to increased expression of the telomerase reverse transcriptase (hTERT) gene, telomerase activity upregulation and TL stabilization. Here we have analyzed the process of spontaneous immortalization of human T cells, regarding pathways involved in senescence and telomerase regulation. Two Nijmegen breakage syndrome (NBS) T cell cultures (S3R and S4) showed gradual telomere attrition until a period of growth crisis followed by the outgrowth of immortalized cells. Whole genome expression analysis indicated differences between pre-, early post- and late postcrisis cells. Early postcrisis cells demonstrated a logarithmic growth curve, very short telomeres and, notably, no increase in hTERT or telomerase activity despite downregulation of several negative hTERT regulators (e.g. FOS, JUN D, SMAD3, RUNX2, TNF-a and TGFb-R2). Thereafter, cMYC mRNA increased in parallel with increased hTERT expression, telomerase activity and elongation of short telomeres, indicating a step-wise activation of hTERT transcription involving reduction of negative regulators followed by activation of positive regulator(s). Gene expression analysis indicated that cells escaped growth crisis by deregulated DNA damage response and senescence controlling genes, including downregulation of ATM, CDKN1B (p27), CDKN2D (p19) and ASF1A and upregulation of CDK4, TWIST1, TP73L (p63) and SYK. Telomerase upregulation was thus found to be uncoupled to escape of growth crisis but rather a later event in the immortalization process of NBS T cell cultures. |
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Authors:
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Sofie Degerman; Jan Konrad Siwicki; Pia Osterman; Kyle Lafferty-Whyte; W Nicol Keith; G?ran Roos |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Aging cell Volume: 9 ISSN: 1474-9726 ISO Abbreviation: Aging Cell Publication Date: 2010 Apr |
Date Detail:
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Created Date: 2010-04-23 Completed Date: 2010-06-10 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 101130839 Medline TA: Aging Cell Country: England |
Other Details:
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Languages: eng Pagination: 220-35 Citation Subset: IM |
Affiliation:
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Department of Medical Biosciences, Pathology, Ume? University, SE-90185 Ume?, Sweden. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Cell Aging* Cell Line Cell Survival Gene Expression Regulation Genome, Human Humans Multigene Family Nijmegen Breakage Syndrome / enzymology*, genetics, immunology RNA, Messenger / genetics Receptors, Antigen, T-Cell / immunology Signal Transduction T-Lymphocytes / cytology, enzymology*, immunology Telomerase / genetics, metabolism* Up-Regulation* |
| Grant Support | |
ID/Acronym/Agency:
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//Cancer Research UK |
| Chemical | |
Reg. No./Substance:
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0/RNA, Messenger; 0/Receptors, Antigen, T-Cell; EC 2.7.7.49/Telomerase |
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