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J. Biol. Chem., Vol. 280, Issue 4, 2863-2872, January 28, 2005

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Regulation of Upstream Binding Factor 1 Activity by Insulin-like Growth Factor I Receptor Signaling^*

An Wu, Xiao Tu, Marco Prisco, and Renato Baserga

From the Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107

The upstream binding factor 1 (UBF1) is one of the proteins in a complex that regulates the activity of RNA polymerase I, which controls the rate of ribosomal RNA (rRNA) synthesis. We have shown previously that insulin receptor substrate-1 (IRS-1) can translocate to the nuclei and nucleoli of cells and bind UBF1. We report here that activation of the type I insulin-like growth factor receptor (IGF-IR) by IGF-I increases transcription from the ribosomal DNA (rDNA) promoter in both myeloid cells and mouse fibroblasts. The increased activity of the rDNA promoter is accompanied by increased phosphorylation of UBF1, a requirement for UBF1 activation. Phosphorylation occurs on a number of UBF1 peptides, most prominently on the highly acidic, serine-rich C terminus. In myeloid cells (but not in mouse embryo fibroblasts) IRS-1 signaling stabilizes the levels of UBF1 protein. These findings demonstrate that IGF-IR signaling can increase the activity of UBF1 and transcription from the rDNA promoter, providing one explanation for the reported effects of the IGF/IRS-1 axis on cell and body size in animals and cells in culture.

Received for publication, June 2, 2004 , and in revised form, October 27, 2004.

^* This work was supported by National Institutes of Health Grants CA 89640 and CA78890. 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: Kimmel Cancer Center, Thomas Jefferson University, 233 S. 10th St., 624 Bluemle Life Sciences Bldg., Philadelphia, PA 19107. Tel.: 215-503-4507; Fax: 215-923-0249; E-mail: b_lupo{at}mail.jci.tju.edu.

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