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J. Biol. Chem., Vol. 277, Issue 38, 35088-35096, September 20, 2002
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From the INSERM Unité 459, Faculté de Medecine Henri
Warembourg, 1 Place de Verdun, Lille 59045, France
The nuclear receptor nurr1 is a
transcription factor involved in the development and maintenance
of neurons synthesizing the neurotransmitter dopamine.
Although the lack of nurr1 expression has dramatic consequences for
these cells either in terms of differentiation or survival, the
mechanisms by which nurr1 controls gene transcription still remain
unclear. In the intent to understand better the modalities of action of
this nuclear receptor, we have undertaken a systematic analysis of the
transcriptional effects and DNA binding properties of nurr1 as a
monomer or when forming dimers with the different isotypes of the
retinoic X receptor (RXR). Here, we show that nurr1 acts as a gene
activator independently of RXR and through an AF2-independent
mechanism. In addition, heterodimerization with RXR is
isotype-specific, involves multiple domains in the C-terminal region of
nurr1, and requires RXR binding to DNA. RXR
Requirements for Heterodimerization between the Orphan
Nuclear Receptor Nurr1 and Retinoid X Receptors*
,
-nurr1 and RXR
-nurr1
heterodimers bind direct repeat response elements and display no
specific requirements with respect to half-site spacing. However, the
retinoid responsiveness of DNA-bound heterodimers requires the
reiteration of at least three nurr1 binding sites, thereby limiting
retinoid-induced nurr1 transcriptional activity to specific direct
response elements.
*
This work was supported in part by a Marie Curie Fellowship
of the European Community Program "Improving Human Research Potential and the Socio-economic Knowledge Base" under Contract
HPMF-CT-2001-01362 (to P. S.) and by the INSERM and Association
France-Parkinson.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Recipient of an INSERM poste vert.
§
To whom correspondence should be addressed. Tel.:
33-3-2062-6876; Fax: 33-3-2062-6884; E-mail:
p.lefebvre@lille.inserm.fr.
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