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Signal Transduction

Identification of novel direct transcriptional targets of glucocorticoid receptor

Leukemia volume 18, pages 1850–1856 (2004)Cite this article

Abstract

Transcription of the genes Granzyme A (GZMA), FK506 binding protein 51 (FKBP5), and Down syndrome critical region gene 1 (DSCR1) is upregulated in leukemic cells upon treatment with glucocorticoids (GCs). Several lines of evidence suggest that these genes are implicated in GC-induced apoptosis upstream of the Bcl-2 family of proteins. These genes were upregulated by GC even in the presence of an inhibitor of protein synthesis, cycloheximide, indicating that they are direct target genes of glucocorticoid receptors. DSCR1 is reported to have four isoforms, each of which has a distinct first exon, E1–E4. Among these isoforms, the one with E1 was selectively upregulated by GC. GZMA and FKBP5 have a cluster of putative glucocorticoid response elements (GREs) in introns 1 and 2, respectively, that was identified to be responsible for the response to GC. They were composed of one complete (A/T)G(A/T)(A/T)C(A/T) sequence surrounded by two incomplete (A/T)G(A/T)(A/T)C(A/T) sequences separated by one to four nucleotides. DSCR1, however, did not have a functional GRE upstream or downstream of exon 1. These studies may lead to improved therapeutic uses of GCs in leukemia and lymphoma based upon the expression of these GC target genes.

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Acknowledgements

We thank Kaori Inoue and Mayu Yamazaki for technical support, Kayoko Saito for preparing the manuscript, and Dr Keith Yamamoto for providing plasmids. This work was supported by Grants for Cancer Research, Genome Research and Child Health and Development from the Ministry of Health, Labour and Welfare; Grant-in-Aid for Scientific Research and the Budget for Nuclear Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan.

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Authors and Affiliations

  1. Department of Genetics, National Research Institute for Child Health and Development, Tokyo, Japan

    M U, L Shen, M Yamada & T Miyashita

  2. Department of Clinical Laboratory, Shanghai Children’s Medical Center, Shanghai, China

    L Shen

  3. Discovery and Pharmacology Research Laboratories, Tanabe Seiyaku Co., Ltd, Saitama, Japan

    T Oshida

  4. Department of Clinical Laboratory, Tokyo Dental College Ichikawa General Hospital, Chiba, Japan

    J Miyauchi

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  1. M U
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Correspondence to T Miyashita.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu).

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U, M., Shen, L., Oshida, T. et al. Identification of novel direct transcriptional targets of glucocorticoid receptor. Leukemia 18, 1850–1856 (2004). https://doi.org/10.1038/sj.leu.2403516

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