title: Distinct functions of Sox2 control self-renewal and differentiation in the osteoblast lineage.
abstract: The transcription factor Sox2 is a key player in the maintenance of pluripotency and "stemness." We have previously shown that Sox2 maintains self-renewal in the osteoblast lineage while inhibiting differentiation (U. Basu-Roy et al., Cell Death Differ. 17:1345-1353, 2010; A. Mansukhani, D. Ambrosetti, G. Holmes, L. Cornivelli, and C. Basilico, J. Cell Biol. 168:1065-1076, 2005). Sox2 also interferes with Wnt signaling by binding β-catenin, a central mediator of the Wnt pathway. Here we show that these multiple functions of Sox2 are encoded in distinct domains. The self-renewal function of Sox2 is dependent on its transcriptional activity and requires both its DNA-binding and C-terminal activation regions, while only the third C-terminal transactivation (TA) region is required for binding β-catenin and interfering with Wnt-induced transcription. The results of gene expression analysis upon Sox2 deletion strongly support the notion that Sox2 maintains stemness. We show also that Sox2 suppresses differentiation by attenuating Wnt signaling by posttranscriptional and transcriptional mechanisms and that adenomatous polyposis coli (APC) and GSK3β, which are negative regulators of the Wnt pathway, are direct Sox2 targets in osteoblasts. Several genes, such as the FoxP1 and BMI-1 genes, that are associated with stemness are downregulated upon Sox2 inactivation. Constitutive expression of the Polycomb complex member BMI-1 can bypass the Sox2 requirement for self-renewal but does not affect differentiation. Our results establish a connection between Sox2 and BMI-1 in maintaining self-renewal and identify BMI-1 as a key mediator of Sox2 function.
authors.affiliation: Department of Microbiology, NYU School of Medicine, New York, NY 10016, USA.
authors.forename: Eunjeong
authors.initials: E
authors.lastname: Seo
authors.forename: Upal
authors.initials: U
authors.lastname: Basu-Roy
authors.forename: Jiri
authors.initials: J
authors.lastname: Zavadil
authors.forename: Claudio
authors.initials: C
authors.lastname: Basilico
authors.forename: Alka
authors.initials: A
authors.lastname: Mansukhani
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000378:metabolism; D000818:Animals; D002453:Cell Cycle / Q000235:genetics; D002460:Cell Line; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D005786:Gene Expression Regulation; D055786:Gene Knockout Techniques; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D051379:Mice; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D010006:Osteoblasts / Q000166:cytology* / Q000378:metabolism*; D010012:Osteogenesis; D063150:Polycomb Repressive Complex 1; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D055748:SOXB1 Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D017384:Sequence Deletion; D015398:Signal Transduction; D012886:Skull; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000235:genetics*; D051176:beta Catenin / Q000378:metabolism
chemical_list: C489421:Bmi1 protein, mouse; C495267:CTNNB1 protein, mouse; D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; C432917:Foxp1 protein, mouse; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse; D051153:Wnt Proteins; D051176:beta Catenin; D063150:Polycomb Repressive Complex 1; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3