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Blood, 1 March 2008, Vol. 111, No. 5, pp. 2606-2614. Prepublished online as a Blood First Edition Paper on December 5, 2007; DOI 10.1182/blood-2007-04-083261. This Article Full Text Full Text (PDF) Supplemental Methods All Versions of this Article: blood-2007-04-083261v1 111/5/2606    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Machado-Pinilla, R. Articles by Perona, R. Search for Related Content PubMed PubMed Citation Articles by Machado-Pinilla, R. Articles by Perona, R. Related Collections Hematopoiesis and Stem Cells Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMATOPOIESIS AND STEM CELLS A dyskerin motif reactivates telomerase activity in X-linked dyskeratosis congenita and in telomerase-deficient human cells Rosario Machado-Pinilla1, Isabel Sánchez-Pérez1, José Ramón Murguía2, Leandro Sastre3, and Rosario Perona1 1 Translational Oncology Unit, Instituto de Investigaciones Biomédicas Consejo Superior de Investigaciones, Cientificas/Universidad Autónoma de Madrid (CSIC/UAM), C/ Arturo Duperier, Madrid; 2 Institute of Plant Molecular and Cellular Biology, Universidad Politécnica de Valencia, Valencia; and 3 Department of Control of Gene Expression Regulation, Instituto de Investigaciones Biomédicas, CSIC/UAM, Madrid, Spain Dyskerin gene is mutated in patients with X-linked dyskeratosis congenita (X-DC), which results in greatly reduced levels of telomerase activity. A genetic suppressor element (GSE) termed GSE24 [NCBI GEO] -2 has been isolated in a screening for cisplatin resistance. GSE24 [NCBI GEO] -2–expressing cells presented impaired telomerase inhibition following in vitro exposure to chemotherapies, such as cisplatin, or telomerase inhibitors. The promoter of the telomerase component hTERT was constitutively activated in GSE24 [NCBI GEO] -2 cells in a c-myc expression–dependent manner. Deletion analyses and mutagenesis of the human c-myc promoter demonstrated that the target sequence for activation was the nuclease hypersensitive element-III (NHEIII) site located upstream to the P1 region of the promoter. Further, expression of GSE24 [NCBI GEO] -2 in cell lines derived from patients with X-DC and in VA13 cells induced increased hTERT RNA and hTR levels and recovery of telomerase activity. Finally, expression of GSE24 [NCBI GEO] -2 was able to rescue X-DC fibroblasts from premature senescence. These data demonstrate that this domain of dyskerin plays an important role in telomerase maintenance following cell insults such as cisplatin treatment, and in telomerase-defective cells in patients with X-DC. The expression of this dyskerin fragment has a dominant function in X-DC cells and could provide the basis for a therapeutic approach to this disease. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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