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J. Biol. Chem., Vol. 280, Issue 2, 1401-1407, January 14, 2005

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The Stem Cell Pluripotency Factor NANOG Activates Transcription with Two Unusually Potent Subdomains at Its C Terminus^*

Guangjin Pan and Duanqing Pei, A CheungKong Scholar of the Li Ke-Shing Foundation¶

From the Institute of Pharmacology, Department of Biological Sciences & Biotechnology, Institutes of Biomedicine, State Key Laboratory of Biomembrane and Membrane Biotechnology, Tsinghua University, 100084 Beijing, China and Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota 55455

Embryonic stem cells are pluripotent progenitors for virtually all cell types in our body and thus possess unlimited therapeutic potentials for regenerative medicine. NANOG, an NK-2 type homeodomain gene, has been proposed to play a key role in maintaining stem cell pluripotency presumably by regulating the expression of genes critical to stem cell renewal and differentiation. Here, we provide the evidence that NANOG behaves as a transcription activator with two unusually strong activation domains embedded in its C terminus. First, we identified these two transactivators by employing the Gal4-DNA binding domain fusion and reporter system and named them WR and CD2. Whereas CD2 contains no obvious structural motif, the WR or Trp repeat contains 10 pentapeptide repeats starting with a Trp in each unit. Substitution of Trp with Ala in each repeat completely abolished its activity, whereas mutations at the conserved Ser, Gln, and Asn had relatively minor or no effect on WR activity. We then validated the activities of WR and CD2 in NANOG by constructing a reporter plasmid bearing five NANOG binding sites. Deletion of both WR and CD2 from NANOG completely eliminated its transactivation function. Paradoxically, whereas the removal of CD2 reduced NANOG activity by 30–70%, the removal of WR not only did not diminish but actually enhanced its activity by 50–100% depending on the cell lines analyzed. These data suggest that either WR or CD2 is sufficient for NANOG to function as a transactivator.

Received for publication, July 12, 2004 , and in revised form, October 20, 2004.

^* This work was supported in part by the Tsinghua University BaiRen Scholar Program, NSFC 30270287, the 973 Project-2001CB5101 (to P. I. Lingsong Li) from the Ministry of Science and Technology of China, and the Tsinghua-Yue-Yuen Medical Sciences Fund. 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.

^¶ To whom correspondence should be addressed. E-mail: duanqing{at}aol.com.

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