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Prepublished online as a Blood First Edition Paper on October 17, 2002; DOI 10.1182/blood-2002-07-2337. This Article Full Text (PDF) All Versions of this Article: 2002-07-2337v1 101/4/1551    most recent Alert me when this article is cited Alert me if a correction is posted 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 HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Ge, Y. Articles by Taub, J. W Search for Related Content PubMed PubMed Citation Articles by Ge, Y. Articles by Taub, J. W Social Bookmarking                   What's this? Submitted August 2, 2002 Accepted October 1, 2002 Transcriptional regulation of the cystathionine-ß-synthase gene in Down Syndrome and Non-Down Syndrome megakaryocytic leukemia cell lines Yubin Ge, Tanya L Jensen, Larry H Matherly, and Jeffrey W Taub* Experimental and Clinical Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Detroit, Michigan, USA Experimental and Clinical Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Detroit, Michigan, USA; Pharmacology, Wayne State University School of Medicine, Detroit, Michigan, USA Experimental and Clinical Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Detroit, Michigan, USA; Division of Hematology/Oncology, Children's Hospital of Michigan, Detroit, Michigan, USA; Pediatrics, Wayne State University School of Medicine, Detroit, Michigan, USA * Corresponding author; email: jtaub{at}med.wayne.edu. Down syndrome children with acute myeloid leukemia (AML), have significantly higher event-free survival rates compared to non-DS AML patients, linked to greater cytosine arabinoside (ara-C) sensitivity and higher transcript levels of the chromosome 21-localized gene, cystathionine-ß-synthase (CBS), in DS myeloblasts. In this study, we examined the transcriptional regulation of the CBS gene in the DS megakaryocytic leukemia (AMkL) cell line, CMK, characterized by significantly higher CBS transcripts compared to the non-DS AMkL cell line, CMS. Rapid amplification of 5'-cDNA ends (5'-RACE) analysis demonstrated exclusive use of the CBS -1b promoter in the cell lines and transient transfections with the full length CBS -1b luciferase reporter gene construct, showed 40-fold greater promoter activity in the CMK than CMS cells. Electromobility shift assays (EMSAs) showed enhanced binding of the transcription factors Sp1/Sp3 to 2 GC/GT-box elements (GC-f and GT-d) in the upstream regions of the CBS -1b promoter in CMK nuclear extracts and undetectable binding in CMS cells. Mutation of the GC-f or GT-d binding site resulted in an approximately 90% decrease of the CBS -1b promoter activity in transient transfections of CMK cells. Chromatin immunoprecipitation (ChIP) assays confirmed in vivo binding of Sp3, USF-1 and NF-YA to the CBS -1b promoter region in chromatin extracts of CMK and CMS cells. Decreased binding of Sp1/Sp3 in CMK nuclear extracts following treatment with calf alkaline phosphatase suggested a role for phosphorylation of Sp1/Sp3 in regulating CBS promoter activity and in the differential CBS expression between CMK and CMS cells. The results of this study with clinically relevant cell line models suggest potential mechanisms for disparate patterns of CBS gene expression in DS and non-DS myeloblasts and may, in part, explain the greater chemotherapy sensitivity of DS AML patients. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: H. Edwards, C. Xie, K. M. LaFiura, A. A. Dombkowski, S. A. Buck, J. L. Boerner, J. W. Taub, L. H. Matherly, and Y. Ge RUNX1 regulates phosphoinositide 3-kinase/AKT pathway: role in chemotherapy sensitivity in acute megakaryocytic leukemia Blood, September 24, 2009; 114(13): 2744 - 2752. [Abstract] [Full Text] [PDF] D. Y. C. Wu, R. Wu, Y. Chen, N. Tarasova, and M. M. J. Chang PMA Stimulates MUC5B Gene Expression through an Sp1-Based Mechanism in Airway Epithelial Cells Am. J. Respir. Cell Mol. Biol., November 1, 2007; 37(5): 589 - 597. [Abstract] [Full Text] [PDF] Y. Ge, A. A. Dombkowski, K. M. LaFiura, D. 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