LIF/STAT3 controls ES cell self-renewal and pluripotency by a Myc-dependent mechanism.
Murine ES cells can be maintained as a pluripotent, self-renewing population by LIF/STAT3-dependent signaling. The downstream effectors of this pathway have not been previously defined. In this report, we identify a key target of the LIF self-renewal pathway by showing that STAT3 directly regulates the expression of the Myc transcription factor. Murine ES cells express elevated levels of Myc and following LIF withdrawal, Myc mRNA levels collapse and Myc protein becomes phosphorylated on threonine 58 (T58), triggering its GSK3beta dependent degradation. Maintained expression of stable Myc (T58A) renders self-renewal and maintenance of pluripotency independent of LIF. By contrast, expression of a dominant negative form of Myc antagonizes self-renewal and promotes differentiation. Transcriptional control by STAT3 and suppression of T58 phosphorylation are crucial for regulation of Myc activity in ES cells and therefore in promoting self-renewal. Together, our results establish a mechanism for how LIF and STAT3 regulate ES cell self-renewal and pluripotency.
Cartwright
Peter
P
University of Georgia, Rhodes Center, 425 River Road, Athens, GA 30602-2771, USA.
McLean
Cameron
C
Sheppard
Allan
A
Rivett
Duane
D
Jones
Karen
K
Dalton
Stephen
S
D000818:Animals; D015152:Blotting, Northern; D002454:Cell Differentiation; D047369:Chromatin Immunoprecipitation; D004268:DNA-Binding Proteins / Q000502:physiology*; D015536:Down-Regulation; D004622:Embryo, Mammalian / Q000166:cytology*; D005434:Flow Cytometry; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D015151:Immunoblotting; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D050796:STAT3 Transcription Factor; D013234:Stem Cells / Q000166:cytology*; D013997:Time Factors; D015534:Trans-Activators / Q000502:physiology*; D014158:Transcription, Genetic; D014162:Transfection
D004268:DNA-Binding Proteins; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3