LRH-1/NR5A2 interacts with the glucocorticoid receptor to regulate glucocorticoid resistance
| Autor: | Svenja Michalek, Thomas Goj, Anna Pia Plazzo, Blerim Marovca, Beat Bornhauser, Thomas Brunner |
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| Přispěvatelé: | University of Zurich, Brunner, Thomas |
| Rok vydání: | 2022 |
| Předmět: |
1303 Biochemistry
Receptors Cytoplasmic and Nuclear Apoptosis 610 Medicine & health Precursor T-Cell Lymphoblastic Leukemia-Lymphoma Biochemistry Receptors Glucocorticoid 1311 Genetics 10036 Medical Clinic ddc:570 Genetics 1312 Molecular Biology Humans Molecular Biology Glucocorticoids Metabolism Inborn Errors Transcription Factors |
| DOI: | 10.5167/uzh-224648 |
| Popis: | Nuclear receptors are transcription factors with important functions in a variety of physiological and pathological processes. Targeting glucocorticoid receptor (GR) activity using glucocorticoids is a cornerstone in the treatment of patients with T cell acute lymphoblastic leukemia (T-ALL), and resistance to GC-induced cell death is associated with poor outcome and a high risk for relapse. Next to ligand-binding, heterodimerization with other transcription factors presents an important mechanism for the regulation of GR activity. Here, we describe a GC-induced direct association of the Liver Receptor Homolog-1 (LRH-1) with the GR in the nucleus, which results in reciprocal inhibition of transcriptional activity. Pharmacological and molecular interference with LRH-1 impairs proliferation and survival in T-ALL and causes a profound sensitization to GC-induced cell death, even in GC-resistant T-ALL. Our data illustrate that direct interaction between GR and LRH-1 critically regulates glucocorticoid sensitivity in T-ALL opening up new perspectives for developing innovative therapeutic approaches to treat GC-resistant T-ALL. published |
| Databáze: | OpenAIRE |
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