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Institut de Génétique et de Biologie Moléculaire et Cellulaire (Centre National de la Recherche Scientifique/Institut National de
la Santé et de la Recherche Medicale/Université Louis Pasteur), F-67404 ILLKIRCH Cedex C.U. de Strasbourg, France
STAT transcription factors are induced by a
number of growth factors and cytokines. Within minutes of induction, the STAT proteins are phosphorylated on tyrosine and serine residues and translocated
to the nucleus, where they bind to their DNA targets. The leukemia inhibitory factor (LIF) mediates pleiotropic and sometimes opposite effects both in vivo and
in cultured cells. It is known, for example, to prevent
differentiation of embryonic stem (ES) cells in vitro. To
get insights into LIF-regulated signaling in ES cells, we
have analyzed protein-binding and transcriptional properties of STAT recognition sites in ES cells cultivated in the presence and in the absence of LIF. We
have detected a specific LIF-regulated DNA-binding
activity implicating the STAT3 protein. We show that
STAT3 phosphorylation is essential for this LIF-dependent DNA-binding activity. The possibility that ERK2
or a closely related protein kinase, whose activity is
modulated in a LIF-dependent manner, contributes to
this phosphorylation is discussed. Finally, we show that
the multimerized STAT3-binding DNA element confers LIF responsiveness to a minimal thymidine kinase
promoter. This, together with our observation that
overexpression of STAT3 dominant-negative mutants
abrogates this LIF responsiveness, clearly indicates that STAT3 is involved in LIF-regulated transcriptional
events in ES cells. Finally, stable expression of such a
dominant negative mutant of STAT3 induces morphological differentiation of ES cells despite continuous
LIF supply. Our results suggest that STAT3 is a critical
target of the LIF signaling pathway, which maintains pluripotent cell proliferation.
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