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J Biol Chem, Vol. 274, Issue 53, 38225-38231, December 31, 1999
From INSERM Unité 459, Faculté de Médecine Henri
Warembourg, 1, place de Verdun, 59045 Lille cedex, France
Retinoic acid (RA) regulation of cellular
proliferation and differentiation is mediated, at least in part,
through two related nuclear receptors, RAR and RXR. RA-induced
modulation of gene expression leads generally to cellular
differentiation, whereas stimulation of the protein kinase C (PKC)
signaling pathway is associated with cellular proliferation. Pursuant
to our discovery that prolonged activation of PKCs induced a strong
decrease in RA responsiveness of a retinoid-inducible reporter gene, we
have further investigated the connections between these two signaling pathways. We demonstrate that PKC isoforms
Serine 157, a Retinoic Acid Receptor
Residue Phosphorylated
by Protein Kinase C in Vitro, Is Involved in RXR·RAR
Heterodimerization and Transcriptional Activity*
,
and 
are able to phosphorylate human RAR (hRAR) in vitro on a single
serine residue located in the extended DNA binding domain (T box). The
introduction of a negative charge at this position (serine 157)
strongly decreased hRAR transcriptional activity, whereas a similar
mutation at other PKC consensus phosphorylation sites had no effect.
The effect on transcriptional activation was correlated with a decrease
in the capacity of hRAR to heterodimerize with hRXR. Thus hRAR is a direct target for PKC and , which may control retinoid receptor transcriptional activities during cellular proliferation and differentiation.
*
This work was supported in part by grants from INSERM, Ligue
Nationale contre le Cancer, and Association pour la Recherche sur le
Cancer. INSERM U 459 is part of IFR 22 (INSERM, Centre Hospitalier
Régional Universitaire, Centre Oscar Lambret, and University of
Lille 2).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 Région Nord-Pas de Calais and CHRU.
§
Present address: Laboratory of Developmental Genetics, Rockefeller
University, 1230 York Ave., New York NY 10021.
¶
To whom correspondence should be addressed. Tel.:
33-3-2062-6887; Fax: 33-3-2062-6884; E-mail:
p.lefebvre@lille.inserm.fr.
Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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