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J Biol Chem, Vol. 274, Issue 52, 37483-37490, December 24, 1999
From the Ludwig Institute for Cancer Research, Stockholm Branch,
Box 240, S-171 77 Stockholm, Sweden and the § Department of
Cell and Molecular Biology, Karolinska Institute,
S-171 77 Stockholm, Sweden
Nurr1, a member of the nuclear hormone receptor
superfamily, was recently demonstrated to be of critical importance in
the developing central nervous system, where it is required for the generation of midbrain dopamine cells. Nuclear receptors encompass a
transcriptional activation function (activation function 2; AF2) within
their carboxyl-terminal domains important for ligand-induced transcriptional activation. Since a Nurr1 ligand remains to be identified, the role of the Nurr1 AF2 region in transcriptional activation is unclear. However, here we show that the Nurr1 AF2 contributes to constitutive activation independent of exogenously added
ligands in human embryo kidney 293 cells and in neural cell lines.
Extensive mutagenesis indicated a crucial role of the AF2 core region
for transactivation but also identified unique features differing from
previously characterized receptors. In addition, Nurr1 did not appear
to interact with, and was not stimulated by, several previously
identified coactivators such as the steroid receptor coactivator 1. In
contrast, adenovirus protein E1A, stably expressed in 293 cells, was
shown to contribute to AF2-dependent activation. Finally,
while the AF2 core of RXR is required for ligand-induced
transcriptional activation by Nurr1-RXR heterodimers, the functional
integrity of Nurr1 AF2 core is not critical. These results establish
that the ligand binding domain of Nurr1 has intrinsic capacity for
transcriptional activation depending on cell type and mode of DNA
binding. Furthermore, these results are consistent with the possibility
that gene expression in the central nervous system can be modulated by
an as yet unidentified ligand interacting with the ligand binding
domain of Nurr1.
Activity of the Nurr1 Carboxyl-terminal Domain Depends on
Cell Type and Integrity of the Activation Function 2*
,
*
This work was supported by Swedish Medical Research Council,
the Children's Cancer Foundation of Sweden and by Karolinska Institute
Funds.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.
Supported by a fellowship from the Gulbenkian Ph.D. Program on
Biology and Medicine and Programa Praxis XXI.
¶
To whom correspondence should be addressed. Tel.:
46-8-728-71-06; Fax: 46-8-33-28-12; E-mail:
thomas.perlmann@licr.ki.se.
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