Nucleic Acids Research Advance Access first published online on February 25, 2007
This version published online on March 27, 2007
Nucleic Acids Research, doi:10.1093/nar/gkm059
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Molecular Biology |
Elevating the levels of Sox2 in embryonal carcinoma cells and embryonic stem cells inhibits the expression of Sox2:Oct-3/4 target genes
1Eppley Institute for Research in Cancer and Allied Diseases, 2Department of Pathology and Microbiology, and 3Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska 68198-6805
*To whom correspondence should be addressed. Tel: +4025596338; Fax: +4025593339; E-mail: arizzino{at}unmc.edu
Received October 16, 2006. Revised January 17, 2007. Accepted January 19, 2007.
Recent studies have identified large sets of genes in embryonic stem and embryonal carcinoma cells that are associated with the transcription factors Sox2 and Oct-3/4. Other studies have shown that Sox2 and Oct-3/4 work together cooperatively to stimulate the transcription of their own genes as well as a network of genes required for embryogenesis. Moreover, small changes in the levels of Sox2:Oct-3/4 target genes alter the fate of stem cells. Although positive feedforward and feedback loops have been proposed to explain the activation of these genes, little is known about the mechanisms that prevent their overexpression. Here, we demonstrate that elevating Sox2 levels inhibits the endogenous expression of five Sox2:Oct-3/4 target genes. In addition, we show that Sox2 repression is dependent on the binding sites for Sox2 and Oct-3/4. We also demonstrate that inhibition is dependent on the C-terminus of Sox2, which contains its transactivation domain. Finally, our studies argue that overexpression of neither Oct-3/4 nor Nanog broadly inhibits Sox2:Oct-3/4 target genes. Collectively, these studies provide new insights into the diversity of mechanisms that control Sox2:Oct-3/4 target genes and argue that Sox2 functions as a molecular rheostat for the control of a key transcriptional regulatory network.
This work was supported by a grant from the National Institute of General Medical Sciences (GM80751). Core facilities used in connection with this work was supported in part by a Cancer Center Support Grant (CA36727). Brian Boer and Janel Kopp were supported in part by Cancer Biology Training Grant (CA09476).
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