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J. Biol. Chem., Vol. 277, Issue 46, 44408-44416, November 15, 2002
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From the The pituitary-specific POU homeodomain factor
Pit-1 likely interacts with other factors for cell-specific expression
of prolactin. Here we identify the paired-like homeobox transcription
factors Pitx1 and Pitx2 as factors functionally activating the proximal human prolactin promoter (hPRL-164luc). Using in vitro
binding assays and a series of site-specific mutations of the proximal hPRL promoter, we mapped the B1 and B2 bicoid sites
involved in Pitx-mediated transactivation of the hPRL-164luc construct.
In somatolactotroph GH4C1 cells, basal proximal hPRL
promoter activity was inhibited by a Pitx2 dominant-negative form in a
dose-dependent manner, whereas binding disruptive mutations
in the Pitx sites significantly reduced basal activity of the promoter.
We also show that synergistic activation of hPRL-164luc by Pitx2 and
Pit-1 requires the integrity of the B2 Pitx binding site, and at least one of the P1 and P2 Pit-1 response elements. In addition, mutation in
the B2 Pitx site results in attenuation of the promoter's
responsiveness to forskolin, thyrotropin-releasing hormone, and
epidermal growth factor. Conversely, Pitx1 or Pitx2 overexpression in
GH4C1 cells leads to an enhancement of the drugs stimulatory effects.
Altogether, these results suggest that full responsiveness to several
signaling pathways regulating the hPRL promoter requires
the B2 Pitx binding site and that Pitx factors may be part of the
proteic complex involved in these regulations. Finally, in
situ hybridization analysis showing coexpression of the
PRL and Pitx2 genes in rat and human
lactotroph cells corroborates the physiological relevance of
these results.
Pitx Factors Are Involved in Basal and Hormone-regulated Activity
of the Human Prolactin Promoter*
,,,, and
Laboratoire ICNE, CNRS UMR
6544-Université de la Méditerranée, Marseille,
France, the § Laboratoire de Biologie Moléculaire
et Génie Génétique, Université de Liège,
Institut de Chimie, B6, 4000 Sart Tilman, Belgium, and the
¶ Laboratoire IFNE, INSERM U501, Marseille, France
*
This work was supported in part by La Ligue contre le Cancer
(2001), the Association pour la Recherche sur le Cancer (Grant 5146),
and CNRS (programme Puces à ADN 2000-2001).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.
To whom correspondence should be addressed: Laboratoire ICNE,
UMR 6544, CNRS-Université de la Méditerranee, Institut
Fédératif Jean Roche, Faculté de Médecine Nord,
Bd. P. Dramard, 13916 Marseille cedex 20, France. Tel.:
33-491-69-89-17; Fax: 33-491-69-89-20; E-mail:
pellegrini.i@jean-roche.univ-mrs.fr.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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