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Título: | Inactivation of CDK6/pRb pathway normalizes survival pattern of lymphoblasts expressin the FTLD-TDP-Progranulin mutation c.709-1G>A. |
Autor: | Alquézar, Carolina CSIC ORCID; Esteras, Noemí CSIC ORCID; Alzualde, Ainhoa; Moreno, Fermín; Sánchez Ayuso, Matilde CSIC ORCID ; López de Munain, Adolfo; Martín-Requero, Ángeles CSIC ORCID | Fecha de publicación: | 18-may-2012 | Editor: | Public Library of Science | Citación: | PLoS ONE 7(5):e37057(2012) | Resumen: | Background Mutations in the progranulin (PGRN) gene, leading to haploinsufficiency, cause familial frontotemporal lobar degeneration (FTLD-TDP), although the pathogenic mechanism of PGRN deficit is largely unknown. Allelic loss of PGRN was previously shown to increase the activity of cyclin-dependent kinase (CDK) CDK6/pRb pathway in lymphoblasts expressing the c.709-1G>A PGRN mutation. Since members of the CDK family appear to play a role in neurodegenerative disorders and in apoptotic death of neurons subjected to various insults, we investigated the role of CDK6/pRb in cell survival/death mechanisms following serum deprivation. Methodology/Principal Findings We performed a comparative study of cell viability after serum withdrawal of established lymphoblastoid cell lines from control and carriers of c.709-1G>A PGRN mutation, asymptomatic and FTLD-TDP diagnosed individuals. Our results suggest that the CDK6/pRb pathway is enhanced in the c.709-1G>A bearing lymphoblasts. Apparently, this feature allows PGRN-deficient cells to escape from serum withdrawal-induced apoptosis by decreasing the activity of executive caspases and lowering the dissipation of mitochondrial membrane potential and the release of cytochrome c from the mitochondria. Inhibitors of CDK6 expression levels like sodium butyrate or the CDK6 activity such as PD332991 were able to restore the vulnerability of lymphoblasts from FTLD-TDP patients to trophic factor withdrawal. Conclusion/Significance The use of PGRN-deficient lymphoblasts from FTLD-TDP patients may be a useful model to investigate cell biochemical aspects of this disease. It is suggested that CDK6 could be potentially a therapeutic target for the treatment of the FTLD-TDP | Descripción: | 8 figuras, 2 tablas | Versión del editor: | http://dx.doi.org/ 10.1371/journal.pone.0037057 | URI: | http://hdl.handle.net/10261/50069 | DOI: | 10.1371/journal.pone.0037057 | ISSN: | 1932-6203 | E-ISSN: | 1932-6203 |
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PLOS_ONE 2012 Martín-Requero.pdf | 3,8 MB | Adobe PDF | Visualizar/Abrir |
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