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Distinct functions of Sox2 control self-renewal and differentiation in the osteoblast lineage.
Mol Cell Biol. 2011 Nov; 31(22):4593-608.MC

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+Show Affiliations

Department of Microbiology, NYU School of Medicine, New York, NY 10016, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21930787

Citation

Seo, Eunjeong, et al. "Distinct Functions of Sox2 Control Self-renewal and Differentiation in the Osteoblast Lineage." Molecular and Cellular Biology, vol. 31, no. 22, 2011, pp. 4593-608.
Seo E, Basu-Roy U, Zavadil J, et al. Distinct functions of Sox2 control self-renewal and differentiation in the osteoblast lineage. Mol Cell Biol. 2011;31(22):4593-608.
Seo, E., Basu-Roy, U., Zavadil, J., Basilico, C., & Mansukhani, A. (2011). Distinct functions of Sox2 control self-renewal and differentiation in the osteoblast lineage. Molecular and Cellular Biology, 31(22), 4593-608. https://doi.org/10.1128/MCB.05798-11
Seo E, et al. Distinct Functions of Sox2 Control Self-renewal and Differentiation in the Osteoblast Lineage. Mol Cell Biol. 2011;31(22):4593-608. PubMed PMID: 21930787.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Distinct functions of Sox2 control self-renewal and differentiation in the osteoblast lineage. AU - Seo,Eunjeong, AU - Basu-Roy,Upal, AU - Zavadil,Jiri, AU - Basilico,Claudio, AU - Mansukhani,Alka, Y1 - 2011/09/19/ PY - 2011/9/21/entrez PY - 2011/9/21/pubmed PY - 2011/12/21/medline SP - 4593 EP - 608 JF - Molecular and cellular biology JO - Mol Cell Biol VL - 31 IS - 22 N2 - 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. SN - 1098-5549 UR - https://www.unboundmedicine.com/medline/citation/21930787/Distinct_functions_of_Sox2_control_self_renewal_and_differentiation_in_the_osteoblast_lineage_ L2 - http://mcb.asm.org/cgi/pmidlookup?view=long&pmid=21930787 DB - PRIME DP - Unbound Medicine ER -