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J. Biol. Chem., Vol. 281, Issue 44, 33497-33504, November 3, 2006

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Germ Cell Nuclear Factor Is a Repressor of CRIPTO-1 and CRIPTO-3^*

Moritz Hentschke¹, Ingo Kurth, Uwe Borgmeyer^¶, and Christian A. Hübner²

From the Institute of Medical Microbiology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany, the Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Butenfeld 42, 22529 Hamburg, Germany, and ^¶Zentrum für Molekulare Neurobiologie Hamburg, University of Hamburg, Falkenried 94, 20251 Hamburg, Germany

The pluripotency of embryonic stem and embryonic carcinoma cells is maintained by the expression of a set of "stemness" genes. Whereas these genes are down-regulated upon induction of differentiation, the germ cell nuclear factor (GCNF) is transiently up-regulated and represses several pluripotency genes. CRIPTO-1, a co-receptor for the morphogen nodal, is strongly expressed in undifferentiated cells and is rapidly down-regulated during retinoic acid-induced differentiation. Although CRIPTO-1 is expressed at very low levels in adult tissues under normal conditions, it is found highly expressed in a broad range of tumors, where it acts as a potent oncogene. We show that expression of CRIPTO-1 is directly repressed by GCNF during differentiation of the human teratocarcinoma cell line, NT2. GCNF bound to a DR0 element of the CRIPTO-1 promoter in vitro, as shown by electrophoretic mobility shift assays, and in vivo, as demonstrated by chromatin immunoprecipitation. Reporter gene assays demonstrated that GCNF-mediated repression of the CRIPTO-1 promoter is dependent upon the DR0 site. Overexpression of GCNF in NT2 cells resulted in repression of CRIPTO-1 transcription, whereas expression of the transcription-activating fusion construct GCNF-VP16 led to an induction of the CRIPTO-1 gene and prevented its retinoic acid-induced down-regulation. Furthermore, we demonstrated that CRIPTO-3, a processed pseudogene of CRIPTO-1 on the X chromosome, is expressed in undifferentiated NT2 cells and is regulated by GCNF in parallel to CRIPTO-1. Thus, our study supports the hypothesis of GCNF playing a central role during differentiation of stem cells by repression of stem cell-specific genes.

Received for publication, July 24, 2006 , and in revised form, August 31, 2006.

^* This work was supported by a grant from the Forschungsförderungsfonds of the University Hospital Hamburg-Eppendorf (to M. H.) and by Grant FG604 from the Deutsche Forschungsgemeinschaft (to C. A. H.). 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 may be addressed. Tel.: 49-40-42803-4663; Fax: 49-40-42803-3250; E-mail: m.hentschke{at}uke.uni-hamburg.de. ² To whom correspondence may be addressed. Tel.: 49-40-42803-4536; Fax: 49-40-42803-5091; E-mail: c.huebner{at}uke.uni-hamburg.de.

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