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PNAS 101 (25): 9272-9276

Copyright © 2004 by the National Academy of Sciences.

Cell Biology

Control of cell size through phosphorylation of upstream binding factor 1 by nuclear phosphatidylinositol 3-kinase

Robert Drakas, Xiao Tu, and Renato Baserga *

Kimmel Cancer Center, Thomas Jefferson University, 233 South 10th Street, 624 Bluemle Life Sciences Building, Philadelphia, PA 19107

Communicated by Hilary Koprowski, Thomas Jefferson University, Philadelphia, PA, May 12, 2004

Received for publication February 2, 2004.

Abstract: The insulin-like growth factor I/insulin receptor substrate 1 axis controls, in a nonredundant way, {approx}50% of cell and body size in animals from Drosophila to mice and in cells in culture. Although other factors may also intervene, cell size is strongly dependent on ribosome biogenesis, which is under the control of RNA polymerase I activity. We have previously shown that insulin receptor substrate 1 (IRS-1) translocates to the nuclei and nucleoli, where it binds to the upstream binding factor (UBF) 1, a regulator of RNA polymerase I activity. Activation of UBF1 requires its phosphorylation. However, IRS-1 is not a kinase, and we searched for an intermediate kinase that can phosphorylate UBF1. We demonstrate here that IRS-1 binds also to the phosphatidylinositol 3-kinase (PI3-K) subunits in nuclear extracts, and that the p110 subunit of PI3-K directly phosphorylates and activates UBF1, an exclusively nucleolar protein. The interaction of IRS-1, PI3-K, and UBF1 in the nucleoli provides one of the mechanisms for the effects of IRS-1 on cell and body size.

Abbreviations: IGF-I, insulin-like growth factor I; IRS-1, insulin receptor substrate 1; MEF, mouse embryo fibroblast; PI3-K, phosphatidylinositol 3-kinase; UBF, upstream binding factor.

* To whom correspondence should be addressed. E-mail: r_baserga{at}

© 2004 by The National Academy of Sciences of the USA

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