Publication: NR4A1, 2, 3 an orphan nuclear hormone receptor family involved in cell apoptosis and carcinogenesis
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Date
2006
Authors
Li, Q.X. ; Ke, N. ; Sundaram, R. ; Wong-Staal, F.
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Publisher
Murcia : F. Hernández
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DOI
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info:eu-repo/semantics/article
Description
Abstract
Three members of the NR4A1/Nur77/
NGFIB orphan nuclear hormone receptor subfamily
(NR4A1, NR4A2, and NR4A3) belong to the steroid
nuclear hormone receptor superfamily. They share
similar structural features and have no known natural
ligand. They constitute immediate early genes that are
induced by serum, growth factors and receptor
engagement and are thus implicated in cell mitogenic
responses. These nuclear receptors are transcription
factors that exert their functions through activation and
subsequent induction of the downstream pathways. They
have been shown to play a role in complex pathways of
cell survival and apoptosis. Although the expression of
these genes have been shown to be pro-survival, it has
also been reported that NR4A1 expression can cause
apoptosis. These two opposite effects apparently result
from distinct mechanisms: either transcriptional
activation of genes responsible for cell survival or cell
apoptosis, or translocation into the cytoplasm where they
target the mitochondria and cause cell apoptosis via Bcl-
2 binding. The latter mechanism constitutes a new
paradigm of cellular apoptosis. In vitro functional
studies using over-expression (gain of function) or gene
inactivation (loss of function) type assays, combined
with transgenic or knockout animal data in vivo, have
revealed these effects and their physiological roles,
including thymocyte development for NR4A1/3 and prosurvival
in CNS for NR4A2. Recent studies have also
suggested an important role of these receptors in cell
transformation and tumorigenicity via both their antiapoptotic
and pro-apoptotic functions. In particular, the
recent identification of a functional ligand for NR4A1
suggests that these members could potentially serve as
drug targets for disease indications such as cancer. While
many aspects of these receptors have been previously
reviewed, this article focuses on new experimentation
and discovery of their apoptotic and carcinogenic roles,
and discusses their potential roles as therapeutic targets.
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