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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.
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NEOPLASIA
Expression of SMRT promotes ligand-induced activation of mutated and wild-type retinoid receptors
Sylvie Côté,
Suzan McNamara,
Daria Brambilla,
Andrea Bianchini,
Giovanni Rizzo,
Sonia Victoria del Rincón,
Francesco Grignani,
Clara Nervi, and
Wilson H. Miller, Jr
From the Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, Montreal, Canada; McGill University Departments of Oncology and Medicine, Montreal, Canada; Department of Histology and Medical Embryology, University "La Sapienza," Rome, Italy; Department of Clinical and Experimental Medicine, General Pathology Section, Perugia University, Italy; and San Raffaele Bio-medical Science Park, Rome, Italy.
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), that 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 silencing mediator for retinoid and thyroid receptors  (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, because 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.
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T. J. Peterson, S. Karmakar, M. C. Pace, T. Gao, and C. L. Smith
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