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Novel dimeric Nur77 signaling mechanism in endocrine and lymphoid cells
A Philips1, S Lesage, R Gingras
1Laboratoire de Génétique Moléculaire, Institut de Recherches Cliniques de Montréal, Québec, Canada.
Abstract:
Within the nuclear receptor family, Nur77 (also known as NGFI-B) distinguishes itself by its ability to bind a target sequence (the NBRE) as a monomer and by its role in T-cell receptor (TCR)-induced apoptosis in T cells. We now report on a novel mechanism of Nur77 action that is mediated by homodimers. These dimers bind a Nur77 response element (NurRE), which has been identified as a target of CRH-induced Nur77 in the pro-opiomelanocortin (POMC) gene promoter. Both halves of the palindromic NurRE are required for responsiveness to physiological signals, like CRH in pituitary-derived AtT-20 cells. Similarly, in T-cell hybridomas, TCR activation induced NurRE but not NBRE reporters. The in vivo signaling function of Nur77 thus appears to be mediated by dimers acting on a palindromic response element of unusual spacing between its half-sites. This mechanism may represent the biologically relevant paradigm of action for this subfamily of orphan nuclear receptors.
Insights
Nur77 (NGFI-B) typically acts as a monomer, but a novel homodimer mechanism is revealed. This dimer form binds a unique Nur77 response element (NurRE), crucial for physiological signaling in T cells and pituitary cells.
Area of Science:
- Molecular Biology
- Endocrinology
- Immunology
Background:
- Nur77 (NGFI-B) is a nuclear receptor involved in T-cell receptor (TCR)-induced apoptosis.
- Nur77 traditionally binds DNA as a monomer to a Nur77-binding response element (NBRE).
Purpose of the Study:
- To investigate a novel mechanism of Nur77 action mediated by homodimers.
- To identify and characterize the DNA response element targeted by Nur77 homodimers.
Main Methods:
- Reporter gene assays in pituitary-derived AtT-20 cells and T-cell hybridomas.
- Analysis of CRH (corticotropin-releasing hormone) and TCR activation effects on Nur77 target gene expression.
Main Results:
- Nur77 homodimers bind a distinct palindromic response element, the Nur77 response element (NurRE).
- The NurRE, not the NBRE, is a target for CRH-induced Nur77 in the POMC gene promoter.
- TCR activation in T cells induces NurRE-driven transcription, not NBRE-driven transcription.
Conclusions:
- Nur77 functions as a homodimer, binding the palindromic NurRE, representing a novel signaling mechanism.
- This homodimer-mediated action on NurRE is biologically relevant for Nur77's role in CRH and TCR signaling pathways.
- This mechanism may be characteristic of a subfamily of orphan nuclear receptors.