Retinoic acid inhibits leukemia inhibitory factor signaling pathways in mouse embryonic stem cells.
Retinoic acid (RA) induces the differentiation of murine embryonic stem (ES) cells to cell types resembling those found in the early embryo. When cultured in the presence of leukemia inhibitory factor (LIF), ES cells are maintained in an undifferentiated (self-renewing) state. Addition of RA to the culture media overrides the self-renewing effects of LIF to induce ES cell differentiation. Therefore, we hypothesized that RA-induced differentiation of ES cells may be accomplished by antagonism of LIF-induced signaling pathways. We demonstrate that RA-induced differentiation of CCE ES cells is associated with (1) downregulation of the LIF receptor (LIFR); (2) decreased tyrosine phosphorylation of signal transducer and activator of transcription 3 protein (Stat3); and (3) increased activation of extracellular regulated kinase (Erk1/2). We conclude that RA induces CCE ES cell differentiation in the presence of LIF, in part, by disrupting signaling between the LIFR/gp130 receptor and nuclear targets that are required to prevent ES cell differentiation. Our data indicate that RA-induced inhibition of LIF signaling does not involve Erk1/2-dependent actions.
Tighe
Ann P
AP
Department of Pharmacology, Weill Medical College of Cornell University, New York, New York 10021, USA.
Gudas
Lorraine J
LJ
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015152:Blotting, Northern; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000378:metabolism; D015536:Down-Regulation; D004622:Embryo, Mammalian; D005786:Gene Expression Regulation; D015850:Interleukin-6 / Q000378:metabolism*; D053605:Leukemia Inhibitory Factor; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; D051379:Mice; D011233:Precipitin Tests; D018121:Receptors, Cytokine / Q000187:drug effects / Q000378:metabolism; D053606:Receptors, OSM-LIF; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013234:Stem Cells / Q000187:drug effects* / Q000502:physiology; D015534:Trans-Activators / Q000187:drug effects / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology*
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; C507838:Lif protein, mouse; C507841:Lifr protein, mouse; D018121:Receptors, Cytokine; D053606:Receptors, OSM-LIF; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D014212:Tretinoin