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Molecular and Cellular Biology, June 2003, p. 3936-3950, Vol. 23, No. 11
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.11.3936-3950.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

A Functional Screen in Human Cells Identifies UBF2 as an RNA Polymerase II Transcription Factor That Enhances the ß-Catenin Signaling Pathway

Dorre A. Grueneberg,1* Lourdes Pablo,2 Kang-Quan Hu,3 Paul August,1 Zhigang Weng,4 and Jacqueline Papkoff5

Aventis Cambridge Genomics Center,1 and Infinity Pharmaceuticals, Inc., Cambridge, Massachusetts 02139,4 Biogen, Inc., Cambridge, Massachusetts 02142,2 Tufts University, Boston, Massachusetts 02111,3 diaDexus, South San Francisco, California 940805

Received 9 August 2002/ Returned for modification 21 October 2002/ Accepted 28 February 2003

ß-Catenin signaling plays an important role in the development of many organisms and has a key part in driving the malignant transformation of epithelial cells comprising a variety of cancers. ß-Catenin can activate gene expression through its association with transcription factors of the lymphoid enhancer factor 1 (LEF-1)/T-cell factor (TCF) family. We designed a screen in human cells to identify novel genes that activate a ß-catenin-LEF/TCF-responsive promoter and isolated the high-mobility group box transcription factor, UBF2. UBF1 and UBF2 are splice variants of a common precursor RNA. Although UBF1 has been shown to activate RNA polymerase I-regulated genes, the function of UBF2 has remained obscure. Here, we show for the first time that both UBF1 and UBF2 activate RNA polymerase II-regulated promoters. UBF2 associates with LEF-1, as shown by coimmunoprecipitation experiments, and potentiates transcriptional activation stimulated by LEF-1/ß-catenin from a synthetic promoter with multimerized LEF/TCF binding sites and a natural cyclin D1 promoter with consensus LEF/TCF binding sites. Downregulation of endogenous UBF expression using an RNA interference approach reduces transcriptional activation of a ß-catenin-LEF/TCF-responsive promoter by means of overexpressed ß-catenin, further implicating UBF as a transcriptional enhancer of the ß-catenin pathway.

* Corresponding author. Mailing address: Aventis Pharmaceuticals, 26 Landsdowne St., Cambridge, MA 02139. Phone: (617) 768-4036. Fax: (617) 374-8811. E-mail: dorre.grueneberg{at}aventis.com.

Molecular and Cellular Biology, June 2003, p. 3936-3950, Vol. 23, No. 11
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.11.3936-3950.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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