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Proteinsignatur der replikativen und prämaturen Seneszenz in humanen nicht-kleinzelligen Bronchialkarzinom- und Fibroblastenzelllinien
Abstract/OtherAbstract :
Recently, it was discovered that the underlying mechanism of tumor regression after anti-cancer treatment cannot be explained with the induction of apoptosis, but rather with a permanent cell cycle arrest termed cellular senescence. We compared two different types of senescence, i.e. telomere-dependant replicative senescence (RS) and premature senescence (PS), whithin two cell strains, the telomerase-positive human non small cell lung cancer cell line A549 and the human fibroblast cell line HK1. By using retroviral vectors, telomerase-suppressed clones could be generated out of the A549 cells, which entered RS after being a certain time in culture. PS was obtained by treating the cells with bleomycin and H2O2 as well as irradiation. HK1 cells were cultured until RS occured and were then compared with transduced cells, which had been immortalized by retroviral overexpression of hTERT, the catalytic subunit of telomerase. Similarily to the A549 cells, PS of HK1 was reached by treating the cells with bleomycin and H2O2. Cell lysates were analyzed using a novel technology, the SELDI-TOF MS ProteinChip Array System, which enables a high through-put and therefore the establishment of a sensitive protein profile of complex biological samples. The generated mass spectra were analyzed onto differential protein expression and several commonly regulated protein peaks in both cell strains as well as variants of cellular senescence could have been found. A protein signature, containing a panel of 12 uniformly regulated protein peaks was detected with 5.0 kDa, 6.2 kDa and 6.3 kDa as being upregulated and 6.7 kDa, 6.9 kDa, 7.7 kDa, 11.3 kDa, 11.5 kDa, 12.3 kDa, 13.8 kDa, 14.0 kDa and 15.3 kDa being downregulated during senescence. Among these peaks was a set of suspected histone proteins, with histone H4 as being clearly identified, which was consecutively downregulated in cells reaching the senescent stage. In conclusion, cellular senescence triggered by telomere dysfunction as well as toxic agents and irradiation unleashes biomarkers, strongly suggesting that there might be a general protein signature of senescence overcoming the barriers of different cell types. The future goal is to identify potential protein biomarkers for detecting senescent cells in vivo, thus providing crucial information about the response to anti-cancer treatment as well as being able to evaluate prognosis in patients.
Authors :
Kloos, Wanda
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Publisher :  Universität Freiburg, Medizinische Fakultät / Universitätsklinikum. Medizinische Univ.-Klinik und Poliklinik     Type :  Text.Thesis.Doctoral     Format :  application/pdf    
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Telomerase, Nicht-kleinzelliges Bronchialkarzinom, Seneszenz, senescence, telomerase, Medical sciences, Medicine
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Languages :  eng    
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