SEARCH:   Advanced

Blood, 15 December 2004, Vol. 104, No. 13, pp. 4226-4235. Prepublished online as a Blood First Edition Paper on August 19, 2004; DOI 10.1182/blood-2003-10-3583. This Article Full Text (PDF) All Versions of this Article: 2003-10-3583v1 104/13/4226    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 Cote, S. Articles by Miller Jr, W. H Search for Related Content PubMed PubMed Citation Articles by Cote, S. Articles by Miller Jr, W. H Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted October 28, 2003 Accepted July 30, 2004 Expression of SMRT promotes ligand-induced activation of mutated and wild-type retinoid receptors Sylvie Cote, Suzan McNamara, Daria Brambilla, Andrea Bianchini, Giovanni Rizzo, Sonia Victoria del Rincon, Francesco Grignani, Clara Nervi, and Wilson H Miller Jr* Department of Oncology and Medicine, McGill University, Lady Davis Institute for Medical Research, Montreal, PQ, Canada Department of Histology and Medical Embryology, University La Sapienza, Rome, Italy Department of Clinical and Experimental Medicine, General Pathology Section, Perugia University, Perugia, Italy San Raffaele Bio-Medical Science Park of Rome, Rome, Italy * Corresponding author; email: wmiller{at}ldi.jgh.mcgill.ca. Nuclear receptors are ligand-modulated transcription factors regulated by interactions with corepressors and coactivators, whose functions are not fully understood. Acute promyelocytic leukemia (APL) is characterized by a translocation, t(15;17), which produces a PML/RAR fusion oncoprotein, whose abnormal transcriptional function is successfully targeted by pharmacologic levels of all-trans retinoic acid (ATRA). Mutations in the ligand-binding domain of PML/RAR that confer resistance to ATRA have been studied by expression in nonhematopoietic cells, such as Cos-1. Here, we show that ATRA binding and transcriptional activation by the same PML/RAR mutant differ markedly between nonhematopoietic and leukemic cell lines. Differential expression of the corepressor isoform SMRT correlates with increased ligand binding and transcription by the mutant PML/RAR. Transient and stable overexpression of SMRT in hematopoietic cells that only express SMRT increased ATRA binding, ligand-induced transcription, and ATRA-induced cell differentiation. This effect may not be limited to abnormal nuclear receptors, since overexpression of SMRT increased ATRA-induced binding and transcriptional activation of wild-type receptors PML/RAR and RAR. Our results suggest a novel role for the SMRT isoform, whereby its cell-specific expression may influence the binding and transcriptional capacities of nuclear receptors, thus providing new evidence of distinct functions of corepressor isoforms and adding complexity to transcriptional regulation. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: T. J. Peterson, S. Karmakar, M. C. Pace, T. Gao, and C. L. Smith The Silencing Mediator of Retinoic Acid and Thyroid Hormone Receptor (SMRT) Corepressor Is Required for Full Estrogen Receptor {alpha} Transcriptional Activity Mol. Cell. Biol., September 1, 2007; 27(17): 5933 - 5948. [Abstract] [Full Text] [PDF]

	Copyright © 2004 by American Society of Hematology         Online ISSN: 1528-0020