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J. Biol. Chem., Vol. 282, Issue 27, 19481-19492, July 6, 2007

This Article Full Text Full Text (PDF) All Versions of this Article: 282/27/19481    most recent M702056200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Li, J. Articles by Pei, D. Search for Related Content PubMed PubMed Citation Articles by Li, J. Articles by Pei, D. Social Bookmarking                      What's this?

A Dominant-negative Form of Mouse SOX2 Induces Trophectoderm Differentiation and Progressive Polyploidy in Mouse Embryonic Stem Cells^*

Jun Li, Guangjin Pan, Kai Cui, Yuwen Liu, Shaobin Xu, and Duanqing Pei¹

From the Institute of Pharmacology, Department of Biological Sciences and Biotechnology, State Key Laboratory of Biomembrane and Membrane Biotechnology, Institutes of Biomedicine, School of Medicine, Tsinghua University, Beijing 100084, China and the Center for Stem Cell Biology and Regenerative Medicine, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510663, China

SOX2 plays an important role in early embryogenesis by cooperating with OCT4 in regulating gene expression in fertilized eggs, yet the precise mechanism through which SOX2 accomplishes this important function remains poorly understood. Here, we describe the identification of two nuclear localization signals (NLS) in SOX2 and the generation of a dominant-negative mutant (Dmu-mSox2) by mutating these two NLS in its high mobility group domain. Characterization of this mutant demonstrated that SOX2 shuttles between the cytoplasm and nucleus using these two NLS. The mutant has lost its ability to interact with OCT4, but remains competent to interact with wild-type SOX2. Functionally, Dmu-mSox2 is inactive and unable to cooperate with OCT4 in transactivating target promoters bearing its binding sites. However, Dmu-mSox2 is able to inhibit the activity of wild-type SOX2 and subsequently suppress the activity of downstream genes such as Oct4 and Nanog. When stably expressed in embryonic stem (ES) cells, Dmu-mSox2 triggered progressive doublings of cell ploidy (>8N), leading to differentiation into the trophectoderm lineage. Knockdown of Sox2 by small interfering RNA also induced trophectoderm differentiation and polyploid formation in mouse ES cells. These results suggest that SOX2 maintains stem cell pluripotency by shuttling between the nucleus and cytoplasm in cooperation with OCT4 to prevent trophectoderm differentiation and polyploid formation in ES cells.

Received for publication, March 9, 2007 , and in revised form, May 15, 2007.

^* This work was supported in part by Grants 30470839 and 30630039 from the National Natural Science Foundation of China, the Tsinghua Yue-Yuen Medical Sciences Fund, and Project 2006CB701500 from the Ministry of Science and Technology of China. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 11-86-20-3229-0706; Fax: 11-86-20-3229-0606; E-mail: pei_duanqing{at}gibh.ac.cn.

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