Leukemia Inhibitory Factor–dependent Transcriptional Activation in Embryonic Stem Cells

Autor: Charlotte Hauss, Claude Kedinger, Fabienne De Graeve, Hélène Boeuf, Nathalie Baran
Rok vydání: 1997
Předmět:
STAT3 Transcription Factor
endocrine system
Transcription
Genetic
Recombinant Fusion Proteins
Cellular differentiation
Protein Serine-Threonine Kinases
Leukemia Inhibitory Factor
Gene Expression Regulation
Enzymologic
Article
Cell Line
Mice
Antibody Specificity
Animals
Phosphorylation
Promoter Regions
Genetic
STAT3
Protein kinase A
Induced pluripotent stem cell
reproductive and urinary physiology
Mitogen-Activated Protein Kinase 1
Lymphokines
Binding Sites
biology
Interleukin-6
Stem Cells
Gene Expression Regulation
Developmental
Cell Differentiation
Cell Biology
Phosphoproteins
Molecular biology
Growth Inhibitors
DNA-Binding Proteins
Blastocyst
Mutagenesis
Calcium-Calmodulin-Dependent Protein Kinases
embryonic structures
Trans-Activators
biology.protein
STAT protein
Tyrosine
Stem cell
Signal transduction
Proto-Oncogene Proteins c-fos
Leukemia inhibitory factor
Cell Division
hormones
hormone substitutes
and hormone antagonists
Acute-Phase Proteins
Zdroj: The Journal of Cell Biology
ISSN: 1540-8140
0021-9525
Popis: 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.
Databáze: OpenAIRE
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