Abstract
NURR1/NR4A2 is an orphan nuclear receptor that is critical for the development and maintenance of mesencephalic dopaminergic neurons and regulates transcription of genes involved in the function of dopaminergic neurons directly via specific NGFI-B response elements (NBRE).and substantial data support a possible role of Nurr1 in the pathogenesis of Parkinson's disease (PD). Here we show that Nurr1 is degraded by the ubiquitin-proteasome pathway and determined that N-terminal region (a.a 1–31) of Nurr1 is essential for an efficient targeting of Nurr1 to degradation in the cell. Nurr1 Δ1–31 has a much longer half-life, and as a consequence its steady-state protein levels were higher, than full-length Nurr1 in the cell. Nurr1 Δ1–31 was as potent as Nurr1 full length in transcriptional luciferase reporter assays after normalization with the corresponding steady-state protein expression levels, either in trans-activation of NBRE or trans-repression of iNOS (inducible NO synthase) reporters. These results suggest that Nurr1 Δ1–31, because of longer persistence in the cell, can be a good candidate for gene and cell therapies in the treatment of PD.
Highlights
NURR1 (Nur-related factor 1, NR4A2/NOT1/RNR-1/HZF3/TINUR) gene, a member of nuclear receptor superfamily [1], [2], is an orphan nuclear receptor that behaves as a transcriptional activator in the central nervous system, and is required for the development of mesencephalic dopamine neurons
And C, the N-terminal flag-tagged Nurr1 has a longer half-life (12–14 h) than the untagged Nurr1 (3– 4 h). All these results show that Nurr1 is degraded by the proteasome pathway with similar half-lives in cells of neuronal origin (PC12) and non-neuronal cells (HeLa) and suggested that the N-terminal region of Nurr1 may be important for degradation, because tagging Nurr1 at its N-terminal region produced an inhibition of its degradation rate in the cell
D and E, the stimulation of an iNos luciferase reporter in RAW264.7 by LPS can be prevented by expression of Nurr1 as described previously [22], and the deletion mutant D1–31 has similar effects as wild-type Nurr1. These results showed that deletion of the first 31 aminoacids of Nurr1 did not modify its ability to promote either transcriptional activation or trans-repression, behaving like Nurr1 full length, and its better performance can be explained by its decreased rate of degradation that resulted in an increase in the steady-state levels of the Nurr1 D1–31 respect to the full-length Nurr1
Summary
NURR1 (Nur-related factor 1, NR4A2/NOT1/RNR-1/HZF3/TINUR) gene, a member of nuclear receptor superfamily [1], [2], is an orphan nuclear receptor that behaves as a transcriptional activator in the central nervous system, and is required for the development of mesencephalic dopamine (mesDA) neurons. It is highly expressed in mesDA neurons during development and throughout adulthood [3] [4] [5]. Nurr functions as a trans-repressor of proinflammatory gene promoters in macrophages, microglia and astrocytes by recruiting CoREST corepressor complex [22]
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