Expression of SMRTβ promotes ligand-induced activation of mutated and wild-type retinoid receptors

• Published in: Blood 2004-12, Vol.104 (13), p.4226-4235
• Main Authors: Côté, Sylvie, McNamara, Suzan, Brambilla, Daria, Bianchini, Andrea, Rizzo, Giovanni, del Rincón, Sonia Victoria, Grignani, Francesco, Nervi, Clara, Miller, Wilson H.
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Hematologic and hematopoietic diseases; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2003-10-3583

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/RARα 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/RARα 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/RARα mutant differ markedly between nonhematopoietic and leukemic cell lines. Differential expression of the corepressor isoform silencing mediator for retinoid and thyroid receptors β (SMRTβ) correlates with increased ligand binding and transcription by the mutant PML/RARα. Transient and stable overexpression of SMRTβ in hematopoietic cells that only express SMRTα increased ATRA binding, ligand-induced transcription, and ATRA-induced cell differentiation. This effect may not be limited to abnormal nuclear receptors, because overexpression of SMRTβ increased ATRA-induced binding and transcriptional activation of wild-type receptors PML/RARα and RARα. Our results suggest a novel role for the SMRTβ 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.